Medical Pharmacology at a Glance doc

Medical
Pharmacology
at
a
Glance
MI
CHA
EL
J . N
EA
L
Professor of Pharmacology
Division of Pharmacology and T herapeutics
Kings Co llege London
The Rayne Institute
51Thoma s's Hospital
London
F
OU
RT H
ED
ITI
O N
Blackwell
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·'''n
Contents
Preface 7
How to use this hook 7
Further reading 7

Introductio n:
principles of drug action 8
2 Drug
-r
ec
eptor
imeracnons 10
3 Drug absorption, distribution and excretion 12
4 Drug metabolism 14
5 Local
anaesthetics 16
fi Drugs acting at the neuromuscular junction 18
7 Autonomic nervous system 20
8 Autonomic drugs acting at cholinergic synapses 22
lJ Drugs acting on the sympathetic sys tem 24
10 Ocular pharmacolog y 26
I I Asthma, hay fever and anaphylaxis 28
12 Drugs acting on the gastrointestinal tract. l:
Peptic ulcer 30
13 Drugs acting on
the gastrointest inal tract. II: Moti lity and
secretions 32
14 Drugs acting on the kidney-cdiuretics 34
15 Drugs used in hypertension 36
16 Drugs usedin angina
3X
17 Antiarrhythmi c drugs 40
18 Drugs used in heart failure 42
19
Drugs used 10affect blood coagu lation 44

20 Lipid-lowering dru gs 46
2 1 Agents used in
anaemias 48
22 Ccnrrulrransrniue r
substances 50
23 Gene ral anaesthetics 52
24 Anx iolytics and hypnotics 54
25 Aruiepileptic drugs
5(,
26 Drugs used in Parkinson's disease 58
27 Antipsychot ic drugs (ncurolcptics) 6()
2R Drugs used in affective disorders
-antid
epre ssants 62
29 Opioid analgexics 64
30 Drugs used in nausea and vertigo (untiemetic sj 66
31 Drug misuse and dependence oR
32
Non-steroidal anti-intlamrnutory drugs ( NSAIDs) 70
33 Cortico steroids 72
34 Sex hormones and drugs 74
35 Thyroid and
antithyroid drugs 76
36 Antidia betic agents
7X
37
Antibacterial dru gs that inhibit nucleic acid synthesis:
sulphonamidcx. rrimcthoprirn. quinolones and
nitroimidazoles 80
3M

Antibacterial drugs that inhibit cell wall synthesis:
penicillin s. cephalosporins and vancomyc in X2
39
Antibacterial drugs that inhibit protein synthesis:
amin ogjycoside s. tetrac yclines, macrolidcs and
chloramphenicol 84
40 Antifungal and antiviral drugs
10:6
4 1 Drugs acting on parasites. I: Helminths (worms) 88
42 Drugs acting a ll parasites, 1I:Protozoa
(}
()
43
Drugs used in cancer 92
44 Poisoning 94
45 Adverse drug
reactions 96
Index
(}H
5
Preface
Thi 1:0* is
nth:"
primarily for m
dical
studc nt-, oot it shou ld
al-e
be
use

fulto
' Iuu 'nl"
and
sci
enn
", in Olh.:r
d
i
'oCirli
~
'" ho wou ld like an
ele ment
al)
' and
concise
i
mrod
uc
non
[0
phannacology.
In thi h
ook
the
I
CAI
ha been
reduce
d to a
min

imum
fOf
unders
tand
-
ing
the
figure Ncv
ertbc
te I haw a1wm r 't.",j in eac h
cha
pter
IU
explam ho

the dru gs produce
tbeir
effec,,,,
and
10outline th
eir
use
In rhi founh edition all
[hi:"
chapl('r. have te
en
updated. A rec
en
t
E

EC
dire
ctiv
e
requires
the U'\C
of
Rec
omm
ende d Internation al Non -
proprie
t
ary
Name
s
Ir
l~N)
for drug For
m.'"
drug
the Briti sh
Propr
ietary
Name
(BAN)
and the rlNN arc lilt" same. bUI where they
differ
, l havc used the new rINN.
This
will ave sluuents having to learn

new names for
drugs a yea r
or
,Il
into their
coursv
bUI may result in
accusations of
had
s[1<;."
lIing until the new names
become
gl'llt'r<llly
familiur.Thc
o:h;
rl1gcs
of n
or
adrenaline to uorepincpltrmc, und adrenaline
'0e
pmcphnnc
. arc likely to he particukuly conn-nnouv. Nevcrth

lcsv,
the new names nrc used .
except
in thc early
chap
ters. whcrc 1hav e gjvcu
hUlh the

r
l~N
and BAN.
How
to
use
this
book
Each or t
tc
chapters (lisled 011 page 51rcprcscmv a part icul
ar
to
pic
.
co
r-
rt:'S
p:,nding roughly to a 6O-minulc lecture.
fk
ginners in pharm acolog y
shou ld slart al Ch
apte
r I and
liN
read through the text on the left-hand
pages
1\00
hich
{lCCa,

iona
ll)
coeun
ue

t
ul
hc facinjl:right-hand page an.,,\c
the
rub!
Iinel
of
severa
l chaprcrv using the ngurc-,
(M
il)
as a
guide
.
Onc e the
genera
l
ooume
hav bee n graspcd. it is
prohal>
l~
better
10
conccmn

te
UlIlhcfi~lIrr
·
.1
nile
<II
a umc.
Some
arc
qeuc
complicated
and
C;III certainly Ill>!
be:
taken in ' at a glance". Each , hould
be:
sludi d care-
fully and worl ed through toge ther
\00
ith Ihc Icgends tright-hand
pagesl
.
Bcc au

man ) d rugs uppeur in more than one cnaprcr. c(Mlsi<krahk
crn

v.refere
ncing
ha

been pr
ovid
e As pro gress is made
through
the
n.,
1(,k
. usc
of
this
cro-v
-rcfcrcnl'ing will pr
ovid
e vuluublc reiuforcerucnt
and a gre ater undcrvtanding of dru g
action
,
Onc
e the info
muuion
has
been
under-
rood .
the
ligu res vhuuld suhcequcmly r
equire
lillie' more
than a

brief
look to refresh the memory,
The ligures are highly diagr.nunuuic and not to scale.
Furth
er reading
}lriti,lh National Fornndorv. Brili,h Medical As
sociation
and '
11
1C
Royal
Pharmac
eutic
al
So
ci
ety of
(jre
.u Britain.
London
(aNl ut
XOO
p
rj.
The
(JI'F
is updated twice a year.
Rang, II.P Dale. M ' !. &.
Rine
r. J.M. ( I

'J')')
IPh<lrm,wology. 41h
ro
n.
Ch urchill Livingvro
nc.
Edinb urgh (X,'ll p
rj.
Ritte r. VII Le wis. L.D .
s:
\I
anl. GX . (199'J l A Tr.l/hoot
of
CUI/in ti
Pharmacology; 4th edn .
Arnold,
Lo
ndlMl
(b!l7 pp).
7
1
Introduction:
principles of
drug
action


-

•• Cellular re6pon6e

S
econ.::l
rneeeenge re _
IF
~
t C<l2.
ACT
IVE
TP.AN
Sf'
0
1<T
Na ' /K· -ATP/.lse
(car
diac glycosides )
Some
drug
S!
inhibit
t
rarll;
po
rt
cecceeeee
Hor
mones
E
NDOCR
I
NE

insu lin
levor hyrodne
cortiso
l
al
doste
rone
te
stos
te
rone
ee tr adiol
LOCAL
hist
amine
se
roto
nin (5HT)
pro
sta
glandins
ION
CHANNELS
,.'
C
a
2
~
charm ele
(Ca channer blockere]

Na- c hannels
(local a
naeet
bet.lce)

-
:.~
••'-
:
-,
._
~~
,
<-
~
6Ii
'
:

-
'
-
Endocrine eland cell
<~
- _~
_-_-
_-_
Som e
drug
e

inhibrt t h
following
Protein
kma
eee
Receptor!
channel
complex

" ' ;
N
e!V
~
t~rrni~
il
l
",
enzy mee
channs!e.
oth
er prot eins
phos phoryl.et ion
,I
au:ty
lcholine
norepinephrine
dopa mine
ee
rctcntn
y-aminobutyric

aCid
(GABA)
glutam
ate
Tr
a
n~mitter
eubet.ancee
-, >", '
acetylcholinesterase
ca rbonic anhyd rase
monoamine
oxidas e
cyclo-oxysen se
Some
drug
e;
inhibit
enzy
mes
ENZY ME INHIBITORS
ant
icholineer era eee
A few dru\3i!l
block
traMlsmitter
i
nactivation
un"KE
BLOCJ;

ERS
••
"
~
0
~,
t ricyc lic
a nt idep
res
sa
n
ts
Medica
l pharmacology is th s
cienc
e
of
chemicals
(drug
,)
that
interac
t
with the
human
bod y.
Th
ese inte ractions nrc divided into IWo l"lasses:
•
pharmn

cod
ynamlcs
. lilt"
CHtd
s
of
the
drug
on the body, and
•
pharmacokinetic
sth
c way the body affects the drug with rime (i.e.
absorption. distribution, mctaholivm and cxcrcriuu).
The
most
common
ways in which a drug can produce its effec ts arc
shown
in the figure. A few drugs tc.g. g
ene
ral anaesthetics, osmotic
diuretics) act by virtue of their physico
chemical
properties and this is
called nOIl.sp
edli
c drug action. Some
drugs
.ICI,I', false

substrates
or
inhibitors for certain tra n
sport
systems (bottom right) or enzymes
tbcnom left). However, most drugs produce their
effects
by acting
Oil
specific protein molecules. usually located in the cell
memb
rane. These
proteins arc called
receptor
s
(
~§
h
and they normally respond to
endogenous chemicals
in
the
body. These chemicals are either synaptic
lra
n
smiller
su bstances
(top
len, +)or
hormon

es (top right, . ). For
example. acetylcholine is a transmitter substance released from motor
nerve endings
and it activuu-s receptors in skd elal muscle. initialing a
sequence of event s that results in contraction 01the muscl e. Chemicals
re.g.
acetylcholine) or drugs
that
acnvute
receptors
ami produce a
response arc called
lI~
(lni st
s
.
Some drugs. called antagonists
(9
),
combine with reccprorx. but do not activate
them.
Antagonists reduce
the probability of the trans mitter substance (or another agonist) com-
bining
with
the re
ceptor
and so reduce or block its action .
The activation of receptors
by an agonist or hormone is

coup
led rothe
physiological or biochemical rcvponscs by transduction mechani sms
(lower tigure)
that
uftcn
(but
not always) involve
molecules
called
's
ec-
und I
UC
Ss('lIl!:t
'r
s-(_ ).
The
interaction
betwe
en a drug and the binding site
of
the
receptor
depends on the complementarity of "tit" of the
tWO
molecules. TIle
closer the lit and the greaterthe
number
ofbonds

(usually non
-covalcnu.
the stronger will he the attractive forces between them , and the higher
the affinit)' of the drug fur the receptor. The ability
of
a drug 10combine
with one part icular type
of
recep tor is called
~
p
("
d
fi
d
t
y.
No
drug
is tru ly
specific but many
have
a relatively s
dedh
l' action on one type
of
rece ptor.
Receptors
These arc protein molecules thm arc norm
ally

activated hy rmnsminers
or hormones. Many receptors have now been
clone
d and their am ino
acid
sequences
determined. The four
main
types
of
recept
or
arc listed
below.
I
Agonis t (Iigan
dj-g
atcd channels are made up
of
protein subunits that
form
a central pore re.g. nicotinic receptor,
Chapter
6: j -uminotiutyric
acid (GA BA) receptor, Chapter
24
~.
2 Gcp
nuein
coupled receptors (sec below) Iorm a family

of
receptors
with
seven membrane-spanning helices. They arc linked (usually) 10
phys iologica l responses by second messengers.
3 Nuclear
receptors
for ste
roid
hor
mones (Chapll'r 34 ) and thyroid
hormones
(Chapter
35) are
present
in the eel!
nucleus
and re
gulat
e
transcription and rhus protein xynthcs!s.
4
Kinase-linked receptors arc s
urface
recep
tor s that posscss (usually)
intrinsic tyrosine
kinase activity. They include receptors f
or
insulin,

cytokincx and
growth factors
(Chapter
36).
Tr
unsm
tne
r suhstunces arc chemicals released from nerve ter-
minals which diffuse across the
synap
tic cleft and hind to th re-
ceptors
. This activates the
receptors
by changing their conformation,
and
triggers a
sequence
of
postsynaptic events resulting in, for exa mple,
muscle contraction or glandular secretion. Following its release, the
transmitter
is i
nactivated
(left
of
tigurc) by
either
enzymic
degradation

re.g. acetylcholine)
or
reuptake te.g. norepinephrine
[nora
drenaline).
GAB
A). Many drugs act by either reducing or enhancing
synaptic
transmission.
Hormones ure che
micnls
released into the bloodstream; they
pro
-
ducc
their physiological effects on tissues possessing th necessary
specific
hormone
receptors . Drugs may interact with the
endocr
ine
sys tem by inhibiting te.g. antithyroid
drug
s, Cha
pter
35)
or
increasing
(e.g. oral
antidiabetic agent"

Chapter
36) hormo ne release. Other drugs
interact with
hormone
receptors that
m(IY
he activated
(c.g
. steroidal
anti-inflanunatory
drug
s,
Chapte
r
~3)
or
blocked
te.g.
oestrogen
untug -
onixts.
Chap
ter 34), L
oc
al
honunucs
(a
utac
oid
s j such :;s

hixtamiuc
.
serotonin (5-hydroxytryptam ine, 5HT), kinins and prostagland ins ur
released in pathological processes.
The
effects
of
histamine can
sometimes
he blocked with antihistamines (Chaptcr 11), and drugs that
block prostaglandin synttwsis (e.g. aspirin) arc widely used as anti-
intlnmmarnry agents (Chap ter 32),
Transport
system
s
The lipid cell
membrane
provides a barrier against the transport
of
hy
drop
hilic molecules
ir
uoor out
of
the cell.
Ion cha n
nels
arc selective pores in the membrane that allow the
ready

transfer
of
ions down the ir electrochemical gradient. The
open
-
closed state
of
these channels is controlled
either
b) the membrane
potential rvohage-gared
channels}or by transmitter substances (lipnnd-
gated channels).
Some
chnrmc!s (e. g, Ca
1
+ channels in the heart) arc
both voltage and transmitter gated.
Voltage-gated
channels
for s\l(!ium,
potassium and calcium have the slime b;tsic structure (Chupter 5) and
,uh
types
exis
t for
lo'ac
h d
ifferlo'n
t

chunnlo'!.
Impnrtant exa mples
of
dr
ug,
that act un voltage-gatl:'d l'hannels
i1rl:'
mlciulIl
d lwmd Mod.e n
(Chapter 10) thm hluck L-typc calcium channels in vascular
smout
h
musde
and the heart , and
{0('<11
ill/<lC
.I'liletin
(Chapter
5) that bloek
~odium
channels in nerves,
Some
ul1Iinll1l"1f{.\(I/II.I' {Chapter 2:'i) and
Drugs are prescri bed to produce a
therapeutic
effect
but they o ften
produce addition
alu
nwun ted l'fTl'

t'lS
(Chapter 45) that range from the
trivial te.g . slight nausea) tn the fata l
(e.g
. aplastic
anaemia
I.
some
antiarrhythmic drugs
(Chan
ter 17) also block Nat channels . No
clinically
useful drug ucts primarily on v
oltage
-gated K+channels hut
oral
antidiabetic drugs act on a
dif
feren t
type
of
K+ channel that is
regulated by
intracellular
adeno
sine
triphosphate (AT P; Ch a
pter
3fi),
Active

tran
sport
pr
ocesses are used to transfer subs tances against
their
concenuuuon
gradients. They utilize special carrier molecules in
the mem brane and
req
uire met
abolic
ene
rgy . Two ex amples arc listed
below.
I Sodium ill/till'.
This
expels Na" ions from inside the cell by a mocha-
nism tlun derivesenergy from ATP and invo lves the
enzyme
adeno
sine
triphospha
tase (A'TPase) .
The
ca
rrier is linked to the trans fer
of
K+ions
into the cell. The
mrdi<i

{, Mly{,V!Jidt's (
Chapter
18) act by inhibi ting the
N
a
~
/K
+
-A
TP
a
s
e.
Na" and/or
Clr
tranxport processes in the kidney arc
inhibited by
somedillrdi
cs (
Chap
ter 14).
2
Nvrl'pilll
'phri/w
transport,
The
Iricydic
({l1Iid
cpl""SM/II1.\"
(Cha pter

2li)
prolong the action
of'nore
pinephrine by hloc king its n-uptake into
l'

nrru!
nerve terminals.
Enzymes
These
are catalytic protei
n,
that increase the
rail'
of chemical reactions
in the
body
. Drugs that act by in
hibitin
g
enzy
mes inc lude: anti-
dlOlilll'.HI'I"U.I'I'.I·, which e
nhance
the action
of
ace
tylcholine
(Chapters 6
and8):

rur/mni
c
anhvdrase
inhibitnrs. which urc diu retics tt.c. increase
urine flow, Ch apter 14 ); monoamine osidasc inhibitors, which are
antidepressants
(Chapte r 28); and inhibitors
of
C
yd()-(IXYf:I
'/l(/.\
1'
(c.g
,
aspirin, Chapter 32),
Second
messengers
These are chemicals whose
intracellular
concentra tion incre ases or,
more r
arely.
dec
reases
in response to
receptor
activation by agon isls,
and which triggl:'r proc
ess
es that e ventu ally result in a cell ular resp onse.

The most studied second
messenge
rs arc;
Ca
2
+ ions,
cyclic
adeno sine
monophospha
te {l'A MP), inositol
-l,4.5
-trbphosphate
(In
sP
, ) and dia-
cylglycerol (OC;),
cA MP is f
orm
ed from AT!' by the
enzyme
udenylyl cyclase when.
for
example.
f3
-adrenoce(lton. are stimulated . The cA MP activates an
enzyme (protein kinase
AI, which phosphoryla
te,
a protein (e
nzyme

ur
ion
chan
nelI and leads to a physiological effect.
InsP, and DG are formed from
membra
ne phos phatidylinositol-
4,S
·bisphosp
hate by activation or a p
hosp
holipase C. Both messen-
ge rs can. like
cAMP, activate kmascs. but Ins!', docs this indirectly
by mobilizing intracellular
calcium stores. Some muscarinic effects
of
acetylcholine and u l-adrenergic effects involve this mechanism
(Chap
ter 7).
(i
-pr
ot
eins
The stimulation
of
adcnylyl cyclase and phosphokinase C following
receptor activation is mediated by a family
of
regulatory guanosine

triphosphate (GT PI-binding
proteins(G-proleins), The
reccp
tnr
~ago
n
ist
co mplex induces a (
onfo
nnat
ional change in the G- protein, causing its
u ,sllbunit to bind GTP. u -
GTP
disso
ciates
from the G-protein :md
al
'tiva
tes
(or
inhibits) the
enzym
e. The sigmll to the elll.yme ends
because u -GTP has intrinsit· U
TP
ase act ivity and turns itself
off
by
hydrolysing the
GT

P to guanosine diphnsp
ll<lte
(GOP).
a-G
OP thcn
r
cassl")(,;ia
tes with the pyG -pf\ltcin
su
buni
t~,
2
Drug-receptor
interactions
Ccncen
tr
at.lcn-reepc nee curve Log
concentra
t io
n-rcspa
n",€:
CUI"\IC
E
ffect
of
antagonist5

",
Part
ial agoni6
u;
" have lower
" maximum
AgOl'li
,,!
conce
ntra
t ion [A]
(eas ier to see maximum and
70% of curve ie st ra ight line)
Pa
rtia
l
aqol'list
,-
"
,
",l
"
Log [A ]
Com
pet
it
ive
ant.agonlet.
/
0

,0
A~rr~v
~
n;
i
b
l
(':
o y .
I I
antag
onist
• 0
Lowdo(>(':
I / High dose
0 ' «"
II
i
0 , J
l P I
o
J'
d ,
,
Log [A]
lntermole
cular
fo
rces
At.jon

ist
Recepto r
Agon
ist/r
(':c
(':
pt
or
complex Tral'ls ducer
Ago
l'l
is
tlrece
pto
rl
traneauc
e- com plex
eie
ct-
oeta
nc
H-bonding
V1
.m der Waal5
hy
dro
phobiC
The tisvues in the body have only
<J
few basic resp onses

when
e
xposed
10 agonists (e.g.
muscle
com rac
non
. glandular
secretion]
and
the
quan-
titative
reknionship
between
th

sc phy s
iologica
l r
esponses
and the
concentration
of
the agonisl can he measured by using hin;
l'
sa ys. The
first part of the dru
g-receptor
interaction. i.c. the binding of drug to

receptor. can be studied in isolation usin g bind in
!/:
lISSl' .
\S
.
It has been found hy experiment that. for
many
tissues and ugonists.
when the
response
is plotted ag,li
n't
the concentration
of
the
drug
, a
curve
is produced rluu is often hyperbolic (cunre
ntr
a
uon-
response
c
urve
. top left). In practice. it is
etten
more conven ient to plot the
response against the loga rithm
of

the agonist concc
nuunon
(Iu!:
CUIl
-
cen
tra
tton- resp
on-e
curv e.
middle
top) . As
sum
ing the interaction
between the drug (A )
andthe
receptor
(R)
(lower figure >obeys the law
of
mass action. then the concentration
of
dru
g-receptor
co mplex (AR>
is given by:
[IIR] '" [R
o
]
[AI

K
n
+ [A]
where R
o
'"
total concentration
of
receptors, A = agonist concentration.
KI)'" dissociation concam.aml AR
'"
concentration
oroccupteo
receptors.
IU
'
B
-
~
Int
rinsic
efficacy
(K
AR
==
a
ffi
n
ity
of AR

co mplex for t ran
sdu
cer)
As this i, the
equation
for a hyperbola. the shape
of
the dos
e-
response
curve
is
explained
if the response is directl y proportional to
[ARI,
Unfortunately, this simple
theor
y docs not explain
another
experi-
mental
tinding-csome
agonists
, called
pa
r
tia
l
agu
nisls, cannot elic it

the
same
maximum
response
,IS
full a!lunists e ven if they have the sume
affinity for the rec
eptor
(top len and middle, - - - ).Thuv, in addition to
having affinity for the
receptor.
an agonist
has
another
chemical
prop
-
erty. cal led i
ntri
ns ic
d
lkm
'~
'
.
which is its ability to elici t a response
whe n it hinds ro a receptor (lower Ilgurej.
A
cnm
p

efiuv
e anla!:uuisl has no intrinsic ctficary and. by occ upying
a proportion
of
the receptors,elfecuvely dilutes the r
cccptor
concemra-
lion.
This
causes
a parallel shift of the log conccnt
rauon-rexponse
curve
tn the
right {top right• • )
butthe
maximum
response is not
depr
essed.
In contrast.
irre
versible an
lag
un ists
depress
the
maximum
response
(top right.

.).
However. at low concentrations. a parallel shift
of
the log
concentrat
ion-response
curve
may o
ccur
without a
reduction
in the
maxi
mum
response (top right. 0 ), Be
caus
e an irreversible antagonist
in effect
removes
receptors from the system, it is
clear
that not all the
receptors nee d
10
be o
ccupied
to elicit the
maximum
response
ti.e.there

is
a receptor r
eserve)
.
Intermolecular
forces
Drug molecules in the c
nvirunmcm
of
receptors are
attracted
initially
by relatively long -range
electrostutic
forces. Then" if the molecule is
suitably shaped
to tit closely to thc binding site
ofthe
receptor"hydro-
gen bonds and van
der
Waals forces briefly hind the
drug
to the rccep-
tor. Irreversible antagonists bind 10 receptors with strong
covale
nt
bonds.
Affinity
This

is a measure
of
how avidly a drug hinds to its receptor. It is
d1,1T
-
acterized by the
equilibrium
dissociation
constem
(K
u)
. which is the
ratio
of
rate constants for the reve rse (k_
l)
and forward (k+11 reaction
between the drug "lid the receptor.
111C
reciprocal
of
K
Il
is
called
the
affinity constant (K
A
)
and (in the abse nce

of
receptor
rese
rve. see
below]
is the
conccmranon
of
drug
uuu
produces .'i()%
of
the
maximum
response.
Antagonists
Most antagonists are drugs that
hind
tn receptors
btu
do not uctivutc
Them
. They may be competitive or irreversible.
Other
types
of
untag-
onist
are less
common,

Cnmpetifiv
e anlaAunisls hind rcvcrvihly with receptors und the
tissue response can he re
turned
10
norma
l by increasing the dose of
agonist. because this increases the probability
of
agonist-receptor
coll isions at the expense
of
untugcnist-cecepror collisions.
111<;:
ability
of
higher doses of agonist to
overcome
the effects
of
the antagonist
results in a par
alle
l sh ift
of
the dose
-response
curve
to the right and is
the

hallmark
of
competitive antagonism.
Irrewr
sihl t'
anta
~uni
s
l
s
have an effect thai cannot he reversed by
increasing the concentration
of
agonist. The only important
examp
le
isphenoxyhf'lI:a/llillf' thm hinds covalently with u -adrenoceptors. The
resulting unsurmountable block is valuable in the
management
of
phaeoc
hr
omocytoma, a tumourthat releases largeamounts
of
epinephrine.
Oth er-types of antagnnls m. Non-compeuuve aut agonl ts do not
bind to the receptor
site hut act
downstream
to prevent the response

[0
,111
agonist. e.g. calcium-channel blockers (Chapter 15).
Che
mica
l anta
gonis
ts simply bind to the active
drug
and inactivate
it. e.g. prolamine abolishes the anticoagulant effect
of
heparin (Chapter
19).
l
>h
) sioluAical
anl
aAlInisl.s arc two agents with opposite effects that
tend to cancel one another
out, e.g. prostacyclin and rhromboxune-A,
on platelet
aggregation (Chapter 19).
Receptor
reserve
In
some
tissues (c.g, smooth muscle). irreversible antagonists initially
shift the log
dose-response

curve
10
the
right without reducing the max -
imum
response, indicating that the max imum response can beobtained
without the agonist occupying all the receptors. The
excess
receptors
arc
sometimes called ',Ifl
llre
' receptors. hut this is a misleading
tcrr
n
because they are
of
functional , ignificance. They increase both the
sensitivity and
speed
of
a system because the concentration
of
drug
-
receptor co mplex (and hence the response) depend, on the product
of
the agonist concentration and the
totat
receptor conccmrunon.

Partial
ago
nist
This is an agonist that
canno
t elicit the same maximu m res
pon
se as a
'full'
agonist.
The
reasons for this art' unknown. One suggestion is that
agonism
depend,
on the affinity
of
the drug
-receptor
complex for
a
transdnrrr
motocutc
(lower
figure). Thus, ,I full agonist produces a
complex
with high uffinuy for the transducer (e.g. the coupling G-
proteins. Chapter II, while a partial agonist
-receptor
complex has a
lower affin ity for the transducer and so

cannot
elicit the full response.
When acting
alone
at
recep
tors. partial agonislS
stimulate
a physio-
logic al
response. but they can antagonize the effects of a full agonist.
This is
because
some
of
the rece ptors previously occupied by the full
agonist become occupied by the partial agonist that has a
smaller
effect
te.g. some
~
-adre
nocep
tor
antagonists. Chapters 15 and 16).
Intrinsic
efficacy
This is the ab ility
of
an

ugomstto
alter the conformation
of
a receptor in
such
a way thai it elici ts a response in the system. II is defined as the
affinity
of
the agonist
-receptor
co mplex for a transducer.
Parfial
a
~u
nisl
s
and
receptor re
ser
ve. A drug that is a partial ago-
nist in a tissue with no receptor reserve may bea fu ll
ago
nist in a tissue
poxscsxing
m:II1Y
' spare' receptors. because its
poor
efficacy
can he
offset hy activating a large r

number
of receptor

t
hant
hat requ ired hy
a full agonist.
Bioassay
Bioassays involve the usc
of
a hio logica
ltis
ue to relate drug
concen-
uution 10 a physiological response. Usually isolated tissues are used
because
it is then
easier
to control the
drug
conce
ntration around the
tissue and reflex responses arc abo lished, However. bioavxays
some-
times involve whole
anima
ls. and the same principles are used in
clinicaltrials. Hioavsuys can
f-c
used to estimate:

• the concentration
of
a drug (largely superseded by chemical
methods]:
• its binding
cons
ranrs: or
•
its potency relative 10another drug.
Measureme
mo
f the relative potencies
of
a series
of
agonislS on diffe r-
ent
tissues has been one
of
the main ways used to classify receptors, e.g.
adrenoceptors (Chapter 7).
Binding
assays
Binding assays are simple und very adaptable. Memh rane fragments
from homogenized
tissues are incubated with radiolabelled drug (usually
·'H ) and then recovered by filtration. After correction for non-specific
binding. the ' Ii- drug bound to the
receptors can be determined and esti -
mations made

of
K
A
and 8
m
»
(number
of
binding Sill'S), Bindin g assavs
arc widely used to study
drug
receptors but have the disadvantage that
no functional response
is measured, and often the radiolabclled drug
does
not hind to a single class
ofrecept
or.
"
3
Drug
absorption
, distribution
and
excretion
IMost
drugs
I
.I
F

irnt
order
TIme
(t
)
IFew druge; I
~O~
d"
.
/
/.
~
s, "' C
o.
- K'l
t
r.c-, ,
Lipid-solubl
,,-,
dr
ugs en
te
r
cells (e.g.
et
hanol)
Highly ionized
drug
s are cc nftned
t o t he

ext
racellular fluid
(e.g. t ubocura rine)
Drugs t h
at
are
highly pro-
tein
-
bound
or high molecular we
l<'j
ht-
(heparin) are retain,,-,d
In
circ
ula t-ion
,1,
1
"
,,'
"
,-
"
"
,-
: / Rena l
:::
glomerulus
'

''
, I
,- . <S
In
tra-
cellu
lar
wa
ter
Int
en;ti
ti
al
water
B+
H
+=
BH'
Volume
of
di"tribution
V
D
.>
M
@)
B
V
~
~

Q'~rrDU;in
.
B B
w •
>l:,.
' bound
BH' drug
Vascular_,
__
~,
-,
•
compar:t:,"e'nt
",0
., _
.v
\
Much uni
onlu
d ( MOH. lo
m'z,.,
d
dm,:!
~e
" b5
or1Jui
d~ug
excre
ud
Urine

I
Distriuu
tion
I I
EK
Cct
n
I
I
I
I
I
I
F
lro;
t
~pa%
I
ml'Ul b
o/i!>.'11
1
""-p
H 8
W I3= BH'
- 1:10
Biliary
dun/
IAb!!lorptlon
Rcutee
of

ad
ministration
,',
~::
:}

Oral - most common
Stomac
h
Buccal cavit y
I
I
I
I
5u l>IIn0Ual
-i
eiflB I
For
e
~amp
l
e
a
~.fr
om
buccat
c.
wity
weakbase (B)
,:;'-

a
VD
id liver I
P' .
(j)
" 7
;-
"
Intravenol'
& in
je-<::t;ion
~
"
'"
- ' ' , _ a void "' "t>,;
orpt
ion
"
i:'
a
rr
l~~
:
r\
"
••
",~,,~,
90%
molecul
e,;;

unlon iz",d -
F
actors
affecting
dr'IJfj
absorption
Formulat ion
Stab
il
ity
t o acid and
enzymes
Mot
ili
ty
of g
ut
Food in
sto
mach
Degree
of first -pass
met abolism
Lipid 50l
LJ
bil
it
y
I
I

Dl':perlds a lot on
t he pK of drug and
pH of envlrcnm ent
Unionized d rug is
much more lipid
so luble't han
ionized
dr
ug
The relat ive
proporttone a re givN1
by (
for
a weak base):
BW
log

= pKa- pH
B
Most dru gs ar
t."
given
orall
y and they must pass through the gut wall 10
enter the bloodstream (left of figure.
c::»
.
This
absorptlun
pH

KCS
Sis
affected
hy man y factors (left) but is usually proportional to the lipid
solubilily
of the drug. Thus. the ahxorpuon
of
unionized mole cules (B)
is favo
ur
ed b
ecuuse
they are far more lipid so luhle than those that arc
ioniz
ed (BH ' ) <
II1
U surrounded by a 'shell" of water
molecules
. Drugs
art'
absorbed mainly from the vmal Iintestine be
caus
e
of
its large surface
u
re
a. This is true eve n f
or
weak

acids (e.g. aspir in), which are non-ionized
in the acid (
Hel
) of the stomach. Drugs absorbed from the gastrointes-
tinal tract entert hep
ort
al circulation (left.
[]
)and some are extensively
metabolized as they pass through the liver (first-pass mcrabolix m].
Drugs that arc sufficient ly lipid soluble to he readily
ubsorted
orally
arc rapidly distributed throughout the
tlI

ly wate r compartm ents
(0
l.
Many drugs are loose-ly hound to
plasma
albumin, and an equilibrium
forms betwee n rhe hou nd
(pH)
and free {H ) drug in the plasma. Drug
thaI
is h
ound
to plasma
proteins

is co
min
ed to the vascular system and
is not uble
In
exert its
pharmacological
actions.
If a drug is given by
hura
c
enou
s Injectlon, it enters the blood and is
r
apidly
dist
rib
ute
d torhe
li
.~su
c
s
,
Byl
ak
ingrepealetlohloll
samples.the
fall in plasma co ncentration
of

the drug with time [i.e. the rate
of
drug
elimination) can be measured (right. top graph). Often the conccntra-
non
falls rapidly at first. hut then the rate
of
decline prog ressive ly
decreases.
Such a curve is called cx ponon
uat
. and this means that. at
any given lime . a const
ant
traction
of the dru g present is eliminated in
unit time,
M:
II1
Ydru gs show an exponential fall in plasma concentration
becau se
the rates at which the
drug
elimination processes work are
th
emsel
ves usually proportional to the concemnuion of drug in the
plasma. The followi ng processes are involved.
I Elimination in the urine by glomerular liltralion (right. E.l).
1 Metabolism. usually by the live r.

-' Uptake by the liver
and
suhsequcm
elimina
tion in the bile (solid line
from liver ).
A
pro
c ess thaI depends on the concentration at any give n time is
called
first
order
andmost
drugs
e xhibit first-order elim ination kine t-
ics. If any
enzyme
system
responsible
for
drug
metab
olism
become
s
s
atu
rated. then the elim ination kinetics change 10zeru
enter
. i.c. the

rate
of
clirninanon proceeds at a constant rate and is unaffected by an
Incr
eas
edc
once
nrranon
orthe
dru
g t
e.g.
e
thanm.
ph
en
ytoin).
12
Roules
of
admini
stration
Drugs can be
admini
st
ered
orally
(If
parenterall
y (i.e. by a nO

I1-
guvtrnmtestina l route I.
Ora
l. Mosl
dru
~
s
are ab
sorbe
d by Ihis r
oute
and
bec
ause
of its co
nve-
nicncc it is tilt-
1110
s1 widely used. However. some drugs (e.g. ben-
zylpenicilJin, insulin) are de
stro
yed h)' the acid or enzym
e,
in the gUI
and must
he
give
n parenterally .
In lr
a

\t'
nlIUs inj
t't
'l i
on
,
The
drug
directly
enters
into
the ci rculation
and h)'pa.s
s<:
' Ihe ahSllrpiioo N ITkrs. 11is used ;
• where a rapid e
ucct
i,
required te.g. f
uro
sem ide in
pulmonary
oedema}
;
for conunuouc edminivtration (infusion):
• for large \'O
lul11':s
: ant!
• for
drug'

Ihal cause I., al lissuc damage if given
l>y
other
routes te.g.
C)101m.ic drugs ),
Intramuscular a nd subcutaneous in
jrtl
iu ns . Drugs in
a<J
ueous
solution
are usua lly
ah<.l>rllcd
fairly rapid ly, but absorption
ca
n be
slowed by giv ing the drug in the form
of
an esrcr te.g. neurolepticd
epot
prcparationv.
Chapter
27).
O
th
er
ro
ult'S include inhalation (e.g. volatile anaesthetics.
MHllt:
drugs u

-d in aslhma) and
t"";
("(
I/ re.g. ointmentv). Suh/ingUilf and rec-
tul admi ni, tr.ltillll avoids the portal circulation. and sublingual p
repar
a-
tions in particular are vaju
ablc
in admi ni
'l
erin
g drugs su
bjec
t to a high
degree of lirsl
.pa
ss m
ela
h
oli
sm.
Distribution
and
excretion
Dislribution annmd me bod y
occ
urs when the drug reaches the circuta-
lion . II mu

stthen
pen
etr
ate li
"u
es to act.
'.
il lhalf· life ) is the lime taken for the concer nralion of dru g in bl
ood
10 fall by half ih original value (righl. lop graph). Measu rement
of
'v
a
allo ws the calc ulation
of
the elimination rate
I"lJllSlal/t
(K
d
)
from the
formula:
nes
K , -
" ,
K
el
is Ihe fr;lclioll of drug prescnl al any limc thai would be e1iminaled
in unil lime
(I

'
.g
, K
ol
'"
0.02
mim
l
l~
1
means that 2%
oftht:
drug
presell1
is eliminall'd in I minule).
The
exp0[lem illl curve
of
phl
\ma
C01KC
l1l
ralion (Cp)
agaiml
lime
(I)
is
d~
scrilx
'd

by:
C
p"'Cue
-
K
cl
'
\lo
here C
II
'" thc initial a
ppar
t
'11l
plasma conce nlralion. By taking loga-
rithm s, lhe
expo.
l1
1{'
lllia
lt·
urve
l;:
an he Imn
sf
unnt:d inlo a mon: conve-
nient
s
t
ra i~

h
t
line (right. h
ollnm
graph) from wh
kh
Co and 'w can
readily be del
emlin
t:d.
V
olum
e
nfd
i
'l
rih
Ulion (VIII.Th is
i\t
he apparenl volume i
mow
hich
lhe drug is distribuk-d. Following an intr.lv
enou
s injection:
\
' _
dO'<
D -
C,

A v31ue
of
1'0 <5 L implic
!>
Ih
all
he drug is n:laincd within the vasc ular
c
ompnrtmcm.A
value < 15 L suggcsts rharrhc
drug
is restricted 10the
cxuu ccllular Iluid.
while large volumes
of
distribution H' D> 15 L)
indicatedist r
ibutiunthrnu
ghoutthc
totalbody wat
cr
or
conccmr
auon
in
certain tivsucs.
TIIC
vo lume
of
dis tribution can be used 10calculate

the
clearance
of
lhe drug,
Ul
earu
nce
is an importum concept in pharmac okinetics. It is the v
el-
ume (If
hlno
d III' plasma cleared of drug in unit time. Plasma clearance
(C/
p
)
is
give
n
bvthc
reta
nons
hip:
Cl
p
= \/
nK
el
The
rare of elu
nination

'" Cl
p
x C
po
Clearance is the sum uf ind ivi
dua
l
cje
ar
aace
values. Thus, C/
p
'"
CI". trnetabohc cle
ar
ance] +Cit crena!
excre
uom.
Clearance. b
UI
nol 11r.' provi
des
an indication
of
lhe ability
of
the liverand kidney 10 dispose
of
drugs.
U

ru
~
dll
.,
a~
t'
,
C1o:arJ.
n(,
:e va
lue!>
can he used 10 plan dosage Iegimens.
Ideally,
in
drug
treatment. a steadY'S1ale plasma coocemrarion
(C
~)
is
required within a known therapeutic range- A steady sietc
Wi
ll he
a hieved 'hen the rate
of
drug
entering
ee sys
tem
ic
circulation

(do!>agerate ]
t:l{
uals the nile of elimination.
Thu
s. the
dos
ing rate '" CI
xC
. This equ ation could he
app
lied 10 an intravenou s inf
u!>ion
hec~ c
lhe
entire
do-c
er
uervthe
circ
ulanon at a k
nown
rate. For
ora
l
admi nistralion. lhe
~
ua
li
Oll
becomes

:
F x
dosc
",-'c
:"-",,=-:::;
'"
CI x C;
aver
age
do
sin
g interval p p
where F '" m/l(/,."i/I./hilit.\·
of
the drug. The ' Ir. value
of
a drug is usc '
ful in
choosing
a do ing interv al t
hat
dues
nOI
produ ce
eJlce"
iv
dy
high peuks Hoxie levels) and low troughs (ineffective leve ls) in drug
concemruno
n.

mm
n
ailab
i l
il~
is a term used 10
desc
ribe lhe proportion
of
udminis-
tered
dru g reaching the sys temic circ ulation. Biouvaila bility is 10
1»
follow ing an
intr
avenous injection fF = I ), but
drug
s are usually g iven
orally and lhe propor
tion
of
the dose reaching
the
sys
te
mic
circulation
varies with different drugs and also
from
patientto

patient. Drugs sub-
jcct
to a high degree
of
first-pas s metabolism may he almost inactive
orally tc.g. glyccr
yltrinitratc,
lidocainc).
Excretion
Ken
ai ex
rr
t'l iull is ullimately
rc~pon,iblc
for the eliminalion
of
mo'l
dru gs. Drugs
<lpIX'ar
in thc glomcrular fillrate, hut if lhey are lipid solu-
l>l
e tlK'y art' re,ldily rca
l>s
orocd in lhe re
nallubulcs
by passive diffusion.
I\-kWholism of
a drug Il
lh
'n n

'suh
s in :l less Iipid
·soluh
le compound.
aidin g ren,ll
cJlue
linn
(Sl'
l'
Chapl
er
4),
The
iOll
izalion
of
weak ,Ici
d,
and bascs d
<:pe
nds on lht: pH
of
lhe
lu
l>
ular lluid. Manipulatioo
of
thc urine pH is sometin
l<:s
useful in

intT
ea
sing renal excrelion. For
exa
mple. biearoonale adminislr.ltion
m,lkes
the u
ritKO
a
lla
line: Ihis
ionil-CS
aspirin. making il les" lipid solu·
ble and increasing its r
olle
of
excrelion.
Weak acid \ and wcak h,lses
an: aclive ly
"'-"l::
n:ted in Ihe proJlimal
lObule , Peoicillins :lre eliminaled by this route.
Uili
a
r ~
exrr
eti u n. Some drugs (e.g. dielh)'lstilbestrol ) are concen-
trJ.
lo:
d in l

ho:
hile and excreled into the intestine when: lhey may be n:ah
sortx-d.
This
clllerohepalic
circ
ulalion increases the pcT"iSlencc of a
drug in
the
hudy
.
13
4
Drug
metabolism
Pr
oduct
ll'
(hydrophilic)
W cee r-et.a
e-a. w",,-ran.,
Incre
ase
m<':tal1ob!lm
of
other
druq
e.
e~.
waria

rin
or
al con
traetpt.ive9
.
.
So
me
dru
ge incre.a5e enl)"T'o(l
&yr'Ith~
(e~.
t>a
rt>i
t
u
ra
~
)
Enzymll
i
n
d
u~o
n
1-
IF,,"et pa!>
!!>
m
etatooll

&m IAll orally ,
n,~Uro':d
dl'Ulll~
paM
th~h
L
~M liver
to
the
¥kmIC
circulauon. Some
, "
"0
completely rnn.tIl>oliu:<l
they
, "
,nac~we
ora!1y-
(e4
, lidocaine. flyceryl
~nnft au)
Some
people
have
.
.
,
~
A few
dnJge

inhilrit t'nzymc& t
I~enzyme
.
.
(e.g,
6Iow
acet-ylaton;)
.
" e.g.cim
ctid
int:. etha
l'\Ol
•
•
.
•
.
.
.
Liver
•
•
.
.
.
•
•
.
PHASE)
•

PHAS E II,
.
ID
~
'
+
M
e
t.
a
l:>
o
l i
~
Conjuga
te
,
•
(lipOphiliC) J
,
Conj ug
ate
,
,
R R
(for
med wi
th
,
,

,
,
,
©
©
,
,
•
endogenou'5
,
-
,
•
rea ct.ant.]
,
,
,
OH
,
,
,
,
TYl'f.5 Of CONJUGMIO"I
,
,
,
RNHCH;, _
RNH
,
,

,
glucuro nide
,
,
< ,
0
,
RCH:2
NH
Z -
'RCHO
,
=<yl
~
,
•
gl
uUt
hione
2
RCR
RCI-'
R'
,
glyc;ine
~
II
I-c
' '
-

,
,
eulphate
-
-
0
OH
-'
-
,
m_
'
PJOR
- Rp;lOH +
Rpl
,
-
-
.
,
.
-
-
-
RCONI-'
R, -
RCOOH
• R,NH
2
:

-
.
.
.
.
.
.
·
,
,
C)'tOChrome
P
-450
·d
e
peru:l
ent
ox:id
ation
AJWI<,<1Inr
H'I'tlIWXYlATJON
pht'not>aro
ita
l
p
ropran
olol
phenytoin
,
s mf

eta
mil'lt
warfar
in
O
XI
DA
TlYE
N· DE
Al"
YLAl ION
mor
phine
f'
·4
50
-INDEPENDlcNT
OXID",nQN
amineox
ida5C
adr
enaline
(epinephrine)
Red uc
t i
o n
m~one
"""""""
Hy
drolyeie

procaine
Be-pirin
lidocaine
Drug me raboliem h;ls 1\\.0 important
eHl'l
'h ,
I The .Irug is
made
mort: h.\"drullhilie- Ihis ha"It'ns its excrc
uon
h)'
111l"
kidneys (righI, .Jbecaus e the It's" lipid-soluble metabolite is
11
1'1
readi ly rCllhsn
rlx
d in the renaltubules.
2 The melllhnlilcs arc usually Ie
s'
active
than
the
parent drug. 1I
11

-
ever. l
hi,
i, nOI

always
so,
aml Sl,rnclimes Ihe ructubolites arc
a,
ucuvc
as (
or
more
acnve
than ) the tlrigin;11 dru g. For ex
amp
le.
diaze
pam
101
drug
used
10 lreal anxiety ) is
mt:laholi/ed
10
nordiazepam
;uk
l
OX;lZI·p<lm
. ht>lh
of
which
are
active
.

I ·
r
nd
ru
~

arc
inactive
umilthcy
arc mt:lahtlliled in the bod y 10 the
ucnvc
drug.
For
exampl
e. Ievod
op
a.
an allliparlin,<{lfIian dru g
IChapl
er
~tll
,
i mcaabofizcd to
dopamin
e.

hik
the
h)
poten

ive
dru g mt.'lhyldnpa (Clt;lpler 151is
metabolized
10
U ·m"'lh) InorepifK'phri
11<'.
The li\ er is the
main
organ
uf
drug
mt,:laholi m
and
is
involved
in
IW"
I!l
·no.
'ral
I) pt
of
reat:lion .
l·h a 1
rt'OI
I"liIJIIS
Thc-,e
involve
Ihe

t>
iOl
r:m~ftl
nn;
lIillll

f a
drug
10 a
more
polar mctab
o-
Iile \It'ft Ilf
ligurel
tJy
intrt>
dul
-ing or u
nnu,
Ling a fu
nclion
al gfilu p (e.g.
011 Nil!, - Sil l.
14
lhi<laliun
s arc the mo I common rcacnons
andthes
e art' cataly cd
hy
.1II

importan
t
cia

of
1"111-)'1111" calledthe
mixed
function
oxida
e
(l'yt
ut.
:hru llU' 1'-45U ). n il" subst rate specificity o f Ihi, enzyme
com-
plcx i, very low and ma ny different drugs can he
oxidized
(I'XllIIll' le ,
l"p
left). Other phase I rcac
uon,
an,' r
eduction
(middle k t'tl anti
hyd rnly

b ( bottom tern.
'·ha II reaction
Drug

or

phase I mcta
bolnc
s. Ihal arc nul suflieicnlly polar 10 he
excret d rapidly by the Li.llley" an:
mad
.:
more
hydrophili
c b)'
cunju\:u
·
rilln wnh endog nou eOlllptlUlltl, in tbe
fiver
(cemrc
of
figure).
Repealed
admim
lralitlfl
of

"Ik:
drug
IIOpl
incrca
'ot:
lhe ,,)'nlhe i
oll
-)
tochroee

P 45tJ
It'n/ yIIll' ind
uctiu
n). Thiv increase the rare
of
Illt:lahoh rn
of
the i
nducing
drug
;m.l alsO
of
olher
drugs
metabolized
h)
lhe
s.:
une enzyme (lop ri
ghn
. In co
ntr
a I.
drug

somc
lime,
inhihil
microsomal enzyme acuvuy
nul'

. D )
and
thi increases Ihe at;lion of
drug

me
tabohzed
by Iht: sa
me
enzyme
ltnp right. J.
In ad.lition 10 these drug
-drug
uue
ra
cuon
s, the melaholi rn of dru g
may
be influenct"d h)' \:t'nt'
tk
fad
nr:o.
Ip
hammcogenctic
l. ilge anti
stlllletJi
:\C
<I
:\C
s. esp

l:da
lly 1
11
0'< ffn :lillg the liver.
Drug
s
A few
drug
s re.g.
gallamine
.
Chapter
61 an:' highl y polar
beca
use they
are fully ionized al physiological pH values. Su
ch
drug
s are melaho-
lized little . if al all . and the termination
of
their al'lion s
depend
s mainl y
un renal excreno
n.
However.
nlOSt
dru gs are highl y lipophilic
and

are
often
bound
to pla sma proleins. As lhe protein-bound drug is nul
fihered at the renal
g
l
(l
m
e
ru
l
u
~
and the free dru g readil)' diffuses !lad.
from the
lubuk
imnthc
blood. such
drug
s wou ld nave a very
pro
lon
ged
action if th
eir
removal relied on renal exeter! n alone. In general, drugs
arc
metabolized to more polar co mpound" which are more easily
excreted by

the kidm-ys.
liver
The main
organ
of
dru g nwtaholism is the liver. !lut other organs. vuch
as the
gas
trointestinal tract and lungv,
haw
(
'nns
i kr.ahle activity. Drugs
given ora lly are usually' absorbed in the small inlesline
and
enter
the
portal system 10 the liver,

here
they may he
e\lcns
i'
-ely metabolized
te.g.
lidocaine.
morph
ine. propranolol). This is calle-djirsl.
pan
mctu-

!lfJIi
" . a term that dt ·s
I10t
refer onl)' ttl hepatic metabolism. For
example.
chl
orp
romazine is metabolized mo
re
in lhe intestine than by
Ihe liver.
Phase
I
reactions
The
most com mon reaction is oxidation. Ot her. relatively uncommon ,
rea
di.
m, arc
red/wli""
and hvdrolvsis,
Mkr
o
soma
l
mlxeu
runctfon
u\ida
sc
sys

tem
~
hny
of
the
enzymes
involved in drug metabolism ure located on the
smooth
endoplasmic
reticulum. whic h
tonne
'111.
1
11
"",i
ele,
when the
ti" uc b homogenized.
These
vesicles
can
be icolatcd !ly differential
centrifugation
and
are called
nncro-omc

\ Ii
CfO'>Ol11.3.i
drug oxidali

on
' in\'Oh'e nicncinami
& ar.knine-dinuc1t."l.lCi
de
phosphate (redu
ced
f
orm
) I
:'ll
ADPH). oxygen and 1

0
le
y enzymes:
(il
ttavoproeem, :'IIADPII
c
)h
x:hrome
P-4~()
reductase:
and
(ii) a
haemo
pnxein.
cytochrome
P-4~O
.
which a :ts as a lerminal n ' i.!asc.

Cylochrome P-4
.'i(
) e' ists in a large numh r
of
, uhtyp<:' (isoenzymes)
wilh
different. hUloflen overlapping. sullslr.lle s
pc'C
i
tk
ities.
Phase
II
reactions
llK"c
usually
on'ur
in
11
ll' liver and involve
".,njuga
tiun
of
a d
mg
I'r its
ph
a
~
c

I rnetahulitc with an t'lldoge nous suhs t.rnce.
Th,
' resulting "lHl-
juga
tes are almost alwa)'s
1o.'ss
active
:111
<1
arc pul:tr
mo
lecu
ks
that arc
re'ldily excreted
hy Ih,' ld drll'ys,
Factors
affecting
drug
metabolism
E
n
/
,
~
mt"
indu
ct iun
Some
drug

s (e.g. ph
rm,h
tlrh
iw
J. c
ar
ha
ma;rpi
"t', rthal/oJ and .
e,pe
-
d ally,
rifampicin) and poUul
ants
(e.g.
p
"
I.
I"l
:,
~
·
lil
·
'
Iwm
mic
h\'dro.,:ar.
!If>n,~
in

tobal_TO
smu
le)
increasc the activily
uf
drug-melaboJilin~
enzymes. The me :han
ir-
ms in
volved
are
unde
.lr bul the che
mic
als
~omeho

affC(:t
, ped tk
D:'>lA
et.juence, 'r-witching o n' the pnxIucliull
"I' the appropriate enZ)
-nl<:
, which b usually a c)'ltlChrome P-45U suh-
tyJ'l!.'(
s). However, nut all c
nLyme,
,ubjcc
lto
induclion

al'{"
mi
<:r
tlsomal.
Fur
example.
hep:tlic
.lko
hol dehydrog,'nase o.:t'urs in the cylop
l'ISIll
.
E
n
l~
'
m
c
inhihitiun
Enzynll' inhihition m'
IY
c.tU\C:1l1vcrse
dmg
inter:Ktions. They tend 10
Ut:cu r
more rapidly Ihan Ihose involving en
/y
me induction hccau\C
lht:}'
occur as soon
a~

tht' inhihiling
drug
I\';u:hn
a high enough
cnnn:
n-
narion
to com pete with lhc affected
drug
. Drug, may inhihit differe nt
f0l111s
of
cytochrome P-45U and
'>0
affect the metabolis m
only
of
drug s
metabolized h)
Ihat particular isoenzyme.C
imnidille
inhibits the mete-
bolism
of

veral potentially roxie dru gs including phenytoin. warfarin
and
tbeophyllinc
. Ervthromvcin a] o inhibits the cytochro
me

P-450
system
and
increa""s the ecu
vuy
tlf theophylline. warfarin, carba-
mazepme
and digoxin.
Gen
enc
pul
ym
orphi
sms
The study
of
how genetic determinants af
fect
drug uction is called
phormocogcnctics, The response to drugs varies between indiv iduals
and,
because the variations usually have a Gaussian distribution. it is
assumed that the dcte
mun
am
of
the response is
multif
actorial. How -
eve r,

some
drug responses show discont inuous variation and in these
cases
the p
opol
:lti"lIIcan bedivided illllltwO or
more
groups. suggesling
a
single-gene poly morphism. An import ant example
of
polymorphism
is debrisoqnine hy
dro
xy/arion. Al\oul R
if
of
the population are
poor
hyd
roxylatorv
and
show
exag
gerated and prolonged responses to drug s
such
a,
propranolol and mctoprolol (Chapter 15}.which und
ergo
exten-

sive hepatic metabolism.
Drug-ocerytating enzymes
H
ep
atic N·ac
et)
lase displays genetic pol
ymorp
hism.
Abou
t 50%
otthe
popu lation acetylarc isomazjd (an unmuberculur
drug)
rapid l) , while
the other
5
11
'.{ acetylate it slowly. Slow acetylation
i_~
caused by an
autosomal recesvive gene lhm is assl iared with decre ased hepatic
N.acetylase activity. Sinw acetylnturs are
more
likely tu uccumuhue
the drug and
to
exper
ience adverse reactions. There is evidence for
polymo

rphism in the acetylation
of
mher
drugs re.g. hydralazine.
procainamide).
Ptosma p
.I('/IlJ
I hotinesrerase
Four
separate genes for this enz)'me o
ccur
at
one
IllCU
s. Rarely t-el :
25(0
). an aty
pica
l furm
"fthe
enzyme oc cu rs and this e
\le
nds lhc
dura
-
tiOll of
acliOll of sux
arn
c tbomum (a
fn."'IlICml

y used neuromuscular
blod.
ing drug ) fr
om
aOOtli
6 m inutes to
o\er
2 hO
UTh
or more .
A
~
t"
Hepalic
micro

oma
l
rnl)
'meS and r"nal nlel'hanisms an:
redu,
'ed at
hirth,
espt:'cially in prctenn
babic~.
Roth systt'ms develop wpidly dur·
ing
thc fi
"'
t four

ee
ls
of
lift'. There .tre var ious melhods for c:
lkula
t-
ing paediatric doses (see Hr;fi .lh
/1/(/1;01/111
f ·omlli/(/ry).
In lht'
dderly.
hepatic met aholism
of
drugs may ix' redlK'ed but
d
C(:
lining rcn.11functinn is
u,ua
lly more irnportanl. B)' 05 years . the
glomerular
filtralion nul.'tG FR h1t'Crea s hy .'l
l'l
. and
ever
y followin g
year
it falls a further 1- 2'l- (as a resull of
ce
ll 10\\

and
decreased ren 1
hlood !low ). Thu s, older people
TlCt.'tI
smaller
d~
of
many' drugs IhaIl
Joe
a ) Ollllger
pcN>rt
, opec-ially cenlrall) acling
drug
s (e.g. opioids,
ix'nzodi;uepirocs, antide pres
<.a
nts). to

hich
the
elderly
~
'
m
to he-
c
ome
m
ore
, n

sili
H;"
th)'
unknown
chan
gl
" in lhe brain).
Met
abo
lismand
drug
toxicity
Occas
iona lly. reao:tive producls of drug mctaholism are tm
de
to various
organs, espt."ci:llly the Ih'er.
Pamn'/Ii/Il
ol.
a

ide ly used
weal
anal-
gesic. n
on
mdl y undcrgoes g lucurllnidnt inn and sulph:llio n. !Iowever,
Ihese prot:esscs
hc"
0

111C
saturatcd at
h
i~
h
tl,,\Cs mid Ihe
dnt
g is then
conjuga
leJ
with glutathione. If the glutathiune supply
h 'CO
Il'll.'S
lkplL-ted.
then a fl'a,'li ve
and potentially
lL-thal
hl'p:lloto:l;ic mc
taho
lite
an
'umu-
l
al
c
~
IChaplcr-Hl.
"
5
local

anaesthetics
Chanrrt:l~
inactivated
8t
~ti"fj
~,.tilll
0n :1
t-ind
~
nlOl>t
",tron!lly to tI
:
a
c
~
i
v
"
r
ed
, ,~
~"wc.aj"e
(unchsr~ed)
Ope"
cn ",.el
Ns'
i
ns
ide
Ou

ts
ide
BH
'
~B+W
IMo:>t anae6thetil;:& I
O
uts
ide
CIoee.::l
Na'
channel
(re&t.i g)
Norma
l
even
t\!;
LO'C
al
ana.,tt
th
eti
c&
C-o
I
o
I
CN,
I
fN,

He"
IChe lTlilt
tly
I
,
,
,
,

b
CH~CH.,
HN
I
co
I
CN,
I
He"
,
,
,
,
I
,
,
6.1
,
,
,
,

,
,
pK.
7.9
-,
7.9
E
ff
e
ct
of
pH
~"'.
lidocaine
-;
prilocaine
ropiv
acai
ne
trupivacain,.;
ESTERS
CQGs
i
l1e
benzoca ine
Utr
aca
ine
procaine ' :
BN'

"'"
- - =
pl:
-
pH
B
e~
.
6
.4-7.4=
1
Thus,
the
ionizedmolecule5 predominate
(10:1)
Moot
local anae5t;het.iGfI
are
weak eaeee
(B)
B + W
~
BW
(protol'latet:l form)
The relative
proportion
of
the
two
formtio

i5 qiyen by:
Local ana cvthcticv
(lop
lcft j (
Ire
drug-, used hIprevent pain by caus ing a
reversible block ofconducuon along nerve fibres. Mosl arc weak bases
thai exist mai nly in a protonatcd form 'II body pH (bottom l
cftt.
The
drugs penetra te the nerve in a non-ionized (lipophilic)form (
.1.
but
once inside the axon. some ionized molecules art' formed and these
block the Na" channels tD ) preventing the generation of ac
uon
pnlt'nli
ab
(lower figure).
All nerve
libre~
an:
sensitive tn 11
>C
<l
l ,
1I1,lt",
the
li<:s
but. in

gcn
c
rut.
-mal t-diameter fibre" ere more sensitive than large fibres. Thus, a d if-
fer
entia
l hlock can be a
chie
ved where the smaller pain and autono mic
fihre" are bjocked, while
coarse
touch
and movement fibre" are spared.
Loca l anaesthetics
val)
widely in their
potency.
duration
of
action. tov-
icity and ability 10
penetrate
mucous
membranes
.
Local anaesthetics depress other excnable tissuo:"
te.g.
myocardium]
if the concentration in the'blood is sufficiently high. but their main sys-
temic effects involve the central nervous system. Synthetic agents pro-

cucc sedation and ligh t-hcaocdncsv. although anxie ty and rcs
lles<,fl('s"
sometimes
occ
ur. presumably
rccau-e
cen
tral inhibitory synapses arc
depressed. Ilighcr tm;ic dost·s
cause
twitching and visual disturbances.
while
severe t
oxicity
causes co
nvul,
io(l\ and co ma. with respiratory
and cardiac depress ion resulung from medullary depression. Even
cocaine. which has central snruuluu t properties
unrelated to its local
anaesthetic action, may
~
'
, I
USl'
death by respiratory depression ,
Lido
caine
is the most widely used agent.
11

acts more rapidly and i,
more stable than most uthcr I,
>c
al uuucsrhctics.
when
gjvcn with
epinephrine. its action lasl,
ah
"u
t'~
O
minutes. Prilo
cnin
e
i
~
similar to
hdoc uine but is more extensively metabolized and i
<,
less tnxic in
equipotent doses. H
upi
vuc
uin
e has a slow onset
(up
til "II minute,,)
but a very lung du
nuiu
n

of
ucuon. up lU X hours when used for nerve
blocks. It i" often
uS<."'II
in pregnancy to produce COlllinuous epidural
blockade during
laboe r. 8(' n
/ll
ca ille is a neutral. water-insoluble.
local
ana<:s
thetic
of
low potency. Its only lise is in s
ur
face a
naes
the ta
for non-inflamed
t i
ss
~
re.g. mouth and. p
hary m
l. Tbc more
to:t.ic
agents. te
tr
ac
ain

e and cocaine. have: restricted use. Cocaine is pri-
marily usetl for surface anaesthesia where
ih
intrinsic \'asocI)rJstrictur
action is
oestrame te.g. in the nosc). Tetracaine drops arc used in
oph thalmology
10
anacsrheuze the cornea.
bettess
toxic drugs such as
,,
\.
~
b
u
p
r
uc
ai
ne
and
pr"
\.~Illt"
t
a
(
'
ai
n

t'
.
which
cause
much less initial
sting ing. are beuer.
1I)'l,."rsensitivit)'
rc
acnun
c
rna)'
occ
ur with lo
ca
l anaesthetics. espe-
cially
in atopic
panen
u. and.
more
ot n with procaine and other
<,s
ters
orn
-
emtnobcnz
oic acid .
NaT
ch
annels

Excitable lissues
pt"'
''CS\ vpccla! voltage-gated Na" channels that
con
sist
of
one
large gtycopnuein
u-subunn
and
some
nmes
t
wo
smaller
I:S
-
suhunil
"
of
unknow n function,
The
II-suhunil has four identical
domain
s.
each
conta ining sh membrane-spanning u -belices (5
1-
56).
The

2-1
cy lindrical helices are stad "etl logether radially in the membr.me
10
funn
a cenma1 channel. Exactly how
volta
ge-
gated
channe ls work
is
110
1 kno wn. but the ir conducta
nce
~
N
a+)
i.\
given
by KNa
T
==
gNa "
nr
1
h.

here g NaTis the maximum con
ducta
nce pos.\ihlc. and m and
h urc ga

ung
c
ons
t
ants
that depend on the
membrane
potential. In the
figure. these
constants arc shown sch

matically as physical g
ates
within
the channel. Al
the resting p
ote
ntial. most h-garcs arc open and the
m-ga tcs arc closed (cl
me
d channel). Depolarization causes the Ill-gates
In
open (
ope
n c
hunnch
hut the intense depolarization of the actjon
porcnrial then
causes
the h-gares to close the channel (inactivation].

This
sequence
is show n in lhe upper half of she figure (J
ef
l 10 righl).
The
m-gate may
correspo
nd
10 lhe
four
posilively c
harged
S-I helices.

hich are thought to
open
lhe
channel
by
mov
ing
outwards
and
roIal-
ing in
response
10
membrane
depolarization. The h-gate responsible

for inac
tiva
tion may he the intracellular loo p connecting the S.l and
55 hel ices:
this swings
into
the internal
mou
th
of
lhe
channe
l and
closes
u.
Action
potential
If enough NaTchannels are opened, rhcn the
1';
111.'
of
Nn" entry into the
axon
exce
eds the rate
of
KTe xit and at this po int, the threshold poten-
tiul,
entry
of Na" ions furthe r

depola
rizes rhc m
embrane.
This
open
s
more Na" channels. res ulting in furth er de
polar
ization that opens
more
NaT cha
nnels
and so on. The fast inward NaTc
urren
t quic kly d
epolur
-
izes
tile me
mbrane
toward,
the NaTeq uilibrium potential (around
+67
mV)
. Then. inactivation
of
the Na" charme b, and the continuing efflux
of
K+ions
cause

repolarizarion
of
the
membrane
.
Fina
lly. the Na' chan-
ncl

regain their
normaltexcitable
" state and the NaT
pump
resrorcv the
10 1
K+
and
removes the
~ained
Xa" ions.
Mechanism
01
local
anaesthetics
Local
anaes
rhenc
s penetrate into the interior
of
the axon in the fu

nn
of
the lipid-so luble free
base
. Th!.'rc.
prultmak
d mull.'(:ules arc fornll"t.!.
which
then
elller
andplu1(
the NaTchann
ds
after hinding to a .
ren'ptor'
(res idues of the S6 transmem brane helix). TIlUs,
quat
erna
ry (fully
protllnatcdj lo
ca
l anaesthl't ics wor k onl y if they art: inje
cted
inside the
nerv
I.'
axon.
U
n~'
hll

rge
d
:tge nts (e.g. ~n
zo
c
ai
n e
)
di

olve in the mem -
hrane
hut the channels arc h
lnt ke
d in an all-or·nolle manner. Thus, ion-
iled
and non -ioni zed
mu
lecules aCI in
I.'s e
ntially tile
same
way (i.e. by
binding 10 a '
fC("
epto
r'
un Ihe Na+!.'hannel). Thi s
'b
locks ' the

chan
nd
.
lar!!ely
by preventing the
upe
ning
ofh
-gate

(i.e. by
inercOL'ii
ng inactiva -
tion).
Evcm
ually. so many
channels
arc inactivalc:d thai their
number
falls
below
the
minimum
necessary for
depolari
la
lion 10 reach Ihrcsh-
old
and
, b<xaus.e action poIemials

cannol
be generated.
11I.'1'"\
'1.'
block
tx:c
u, ,.
Local anaeslhclics arc ·u
e
dep<:ndenl ' (i.e. lhe
degree
of
block
is
propol1
ionall
o Ihe r.l
lco
f
nerve
stimulali
on)
. Thi s indi
l;:
at
cs
Ihal more
drug
mo
ll.'(:ules(in the ir

proto
naled fo
nn
)enter the Na+
chan
nd

\I'hen
Ihey art:
open
and ca use
more
inactivation .
Chemi
stry
COlllllltlllly used hll.·al aml<
'sth
elics con siSlnf a lipophili c end (often an
aromatic ring) and a h
ydrop
hilic
I.'
nd (usually a scconda!)' or Il'n iary
amine). con nected
by an int
er
me
diate
cha in that incorporates an
este

r or
amide
lin
kage
.
Ette
cts
These ma
ybe
:
I Meal and include nerve
blockade
and direct
effects
on vascular
s
mOOl
h me-ere:
1 regional,
co
mprising l
os
s
of
scnsalioos (pain. temperatu re. touch)
and
vasomotor
tone in meregion supplied by the
bloc
ked nerves: and

.l systemic. occurring because ofa""-xption or
i111r
.lVe
nOUS
admin
btr
.llio
n.
He a
rl
The etT

cts of
lo
cal
anaesthetics on the
hran
arc discussed ill Chapt er
17.
Cardia
c to xicity
prob
ably
dtJt:s not
occ
ur in subconvulvive d
ose
s.
Yacc
ular

smoo th
musc
le
The local effects vary. L'oc
ain
e is a vasoconstric
tor
(beca
use it hloc ks
norc
pincphine
reuptake
and potentiates
sympat
hetic
acuvhy)
.

hile
procaine
is a vasodilator, \ 10 1
<Im
ido
cause
vasocons
iricnon
at 10w
concent
ration,
and vasodilatation at hi

gher
c
once
ntrations.
Pril'
l("
ain
l'
is
rnos
tlikely
10
produce
vasoccn-mcuon at
clinica
l
dose

.
follo
w
ed
b)'
lidocai
ne
and
bupivncaine
. The
regitJTl
al effect is vasodilatation

caused
by bl
ocka
de
of
sympathetic
nerves
.
Unr
ali
on o
facl
ion
In gene ral. high potency and long
dura
tion are related 10 high lipid sol-
ubility bcC:IU'< Ihis re
sults
in much
of
the locally applied dru g entering
the
cells. v aso
con
smcuon
ah
o lends to prolong the anaesthetic effect
by reducin g systemic dis tribu
no
n

of
the
agem.
and this can beachieved
by the addiuon of a vasoconstrictor such as e
pinep
hrine
(adre
naline) 0
1'
_
I

ss often . norepinephrine [n
oradre
naline).
Vasoco
nst rictors musl not
be used for
producing
ring
-bloc
k
of
an extremuy
te.g
. linger
or
toe)
because they may

cause
prolonged
ischaemia
and
gangrene
.
Amidev are
tkalk
)la
ted in the liver and e

ters (not
cocaine
) are
hydrolysed
b)
plasma
pse udocholinesterase. oot
drug
metabolism
has
lillIe effect on the durutjcn
of
acuon
of
agents actually in the tissues.
Methods
01
adm
inistration

Sur
face
a n
at'sl
ht'si a
Topical
app
liciltion to cl\tc mal ur mu

oslll surfac!.'s.
In fillrOllinll a Illiesl ht'sia
Subc ut
aneous
injection to act on local nl
'rv
c end ings. usually with a
v
asoco
nsiriclllr.
:'<ler\ e
hlo
ck
Tec
hniqOt':s
r.lT1g
e from infillrdlion
of
anacs
locl
il;:

aro
und
a single ner\"(:
(e. g. dental
anaes
lhesia)to
epidural
and spinal anaestht.'",ia. In spinal
anaesthesia
(inlralhecal block) a
drug
is injected
into
the
cerebrosp
inal
fluid in the suhar.tehnoid space. In epidur.ll
anaes
lhes
ia the anat'sthelic
is inj
cr
ted oulsidc the d ura. Spinal anaeslhesia is te
ch
nk ally far eas ier
to prod uce Ihan epidura l anaesthesia. bU
ltlle
lalt
er
l

crhn
ique vil1ually
elimina
lCS
Ihe J'H)stanac,thetic eOmpliCalill
l1
.

such as
heada
l'he.
Inira
wn
ulis
rc~
i
lllli
l l
ana
esl
ht'
i'ii
a
An:u:sthet ic is injn ·ted intravl.'nou

ly into an
exs
ang uinated limb. A
1
0um

iquL'l preve11l'the age nt rcach ing lhe systemic ci rculation.
17
6
Drugs
acting
at
the
neuromuscular
junction
Nec
rcmuecular
blockl,,!!
drug5
,
,
,
,
"
"
"

'.



"
"
Slow ::
d
J!>OOC

kIltJon
,:,:
DEf'OlAI1:IZING
!>U
l<8
rn~
honiu
rn
C(lMF'EllTI\IE
/-
tul7oGura ri
"t"
galla mi
ne:
PSr!
curon
ium
vecum nium
arracuncm
rcccrcnfum
u
"
"
"
"
"
"
"
"
"

"
"
"
"
"
"
"
"
"
"
"
"
"
"
"
"
"
•
' ,
pYrielostigmme
ne
oot
igm
iM
d i
st
il'lmlne
edrop
honlum
I\N1lCHOLI

NI'f,fEV6<:S
Cholinergic
n~rve
~rmin
al
Ag
ent
e
that
reduce
ACh reiea ee
P
otentiate
t
ran
llm
l
ll
lli
on
Acuon potentials arcconductedi
l111llg
the motor nerves II' their terminals
tupper figure. 0 J whn!:" the
dcpolnrivauon
initiates an intlux
OfCI
)+
ions und the rclc.oc of ;Ii'c
t)

k hulilli' l
ACh)
by a process of
C\uQ
lnsis
t
q)
, The acc
tylchohne
diffuses
aero"
th
o:
junctio
nal
deft
and hind"
to receptors located on th

surface of [he rnu-cje-fibre membrane at
the motor

ndplatc.
T1lI:
reversible combinatio n of accrykholine and
recept
ors (lowe r ligul\' , 0
1l
riggc
Th

ltw
ope
ning
of
cation
-
sele
ctive
channels
I11
1h

cudplarc membrane. allowing an influx of Na+ions and
a lesser efflu x of K' ions. The rcsulling dcpulurizatuur. which is called
an
cnd
plate pOle'liial (EI'
!')
, dep
ola
ri/es the adjacent
muscle
-fibre
memb
rane. If I
"r
ge
enoug
h. this d
<,p

u lari/
<ll
ion results in an action
potential and mU"l.'ll· c
omr
acuon, The acety tc
hulinc
rclca-cd
into
lhe
synaptic
clcrt is rapidly hyd
mly-c
d by' an
enzyme.
acerylcholincvtcr-
ase I E'Jl, which is present in the
cudplatc
mem br
ane
cltl»(' In the
receptors.
N
euromus
cular
tranvmiv sion cun he increased by
ant
kllU li,w
sll
'ra

se
dru
gs t
bouom
lcff}, which inhibit
acetylc
h
oline
st
erase
and slow d
own
the hydrolysis
of
acetylcholine
in the cynapricclef! (see
als"
Ch"ple
rS\
.
Nl'
OJ/ixmilw
and
f,.\
'rill
o.nixm
illl'
are
USl.'
d in

thl."
ue
annen
r
tll
lll
~
a
s
l
h
t'
n
i
a
J:r
a\
is and 10 reve rse competitive neur
omusc
ular bloc kade afte r surgery .
Overdosage
of
anticholiucsrcr.u,c results in cxcc
s,
ac
rtylchohnc
and
a dep
olarization
blo

ck
of
motor
cndplate
s (' dlO lir1l'rgic cr isis'). 'Ow
mu-curinic cffcctv of acetylcholine
("-<'I.'
Chuprcr 7) arc
also
p otentiated
hy
antk
hol illC"lerases but are h
lod
eo with atropine. Edrophonium has
a very sho.,
acuon
and is on ly used 10
diagnose
myasthenia
gravis
.
;'I;
l
'uw
mu
"l.·u
lar
blll(:kiug
dr

ugs (righlj an: u

by tU
);J<'>,
lhetists In re-
la\
s"de
lal lllllsc
iesdu
ring su
rp.Ie
,,1
opcr
arion-,
andh I prevent mu-cle cou-
tnll'ti,ms dur
in
g clc
ci
roconvulsivc therapy
(ECT
), M O' I
of
the clinically
useful ne
uromus
cular
h
lol'
~i

llg
,lruP.st:o
l11
!X'le with acetylcholine for the
rcccpror hUI
do
not inuiarc
ionc
hannel ope ning.
These
cnmp
etittve un -
t
:l~
(l
n ish
ft ucc the
cndplatc
dcpolarizat ions p
ro
du
ced by ace tylc holine
10 a
sil
l' lhal is below lhe rnre hllid for muscle action IX)ICnlialgeneration
and

, '·au"Ca flaccid paral)"i".
I
ll

'l
x,
la
r
il
in
~
hl"l
:k
eN
al l uct on acetyl-
choline rcccptorv.bu
tmggcrthc
opening of the ion channel They are not
reversed by nnticholinestcruw s.
S
u\
anlt'thnniulII is the only drug of this
type
used clinically .
Some
ugcms
(lop
left) ,!l'l presynaptically ,Inti bloc k neur
omusc
ular
tranxmisvion by prevennng lhe
release
of
accrylchotine

.
"
Acetvlchotme
Acetylcholine
i~
synthesized in
motorncuronc
terminals from
choline
and uccrylcocnzymc-A by the
enzyme
choline
acetyltransferasc. The
choline is taken up into the nerve
endings
from the
extracellu
lar tluid by
a special choline carrier located in the terminal
membrane
.
E
XllQlo
sis
Acetylcholine
is stored in
nerve
terminals
in the
cytopla

m anti within
synaptic vesiclesthatarc anchored to thecyto kelctnlnetwork by a protein
ca lled synapsin. When an action potential invades the terminal,
Ca
~
+
inns
enter
and activate a protein
kinase
that phosphorylates synapsin. This
results
in the detachment of vesicles from their anchoring and fusion with
the presynaptic
membrane
.Several hundred 'packets' or 'quanta'
of
acetyl -
choline are released in about a millisecond.
This
is called quarual release
and
is very sensitive 10the extracellularCa -" ion concentration. Divalent
ions.
such as Mg
2+,
antagonize Ca
z
+influx and inhibhrruncmitrcr release,
Ac

etylcholine
receptor
This
can heactivated by nicotine and for this reason is called a
mconnt
c
rec
eptor
.« The
receptor-channel
complex
is pentameric and is con -
structed from four different protein
subunits
(Uul31r in the adult) that
span
the
membrane
and arc
arranged
to form a central pore (channel)
through
which
cations
(mainly Na+)
now.
Acetylcholine
molecules
bind to
the

two
rr-subunits inducing a con rorm.nlonat
change
that
opens
the channel for about I millisecond.
Mya
sthenia
gra
vis
Myasthenia gravis is
,III
autoimmune
disease in which
neuromuscular
transmission is defective.
Circulating
heterogeneous
immunoglobulin
G (
lgG)
antibodies
cause
a loss
of
functional
acetylcholine
receptors in
skeletal muscle. To counteractthe loss of.
or

damage til. receptors, the
amount
of
acetylcholine in the synaptic
cleft
is increased by the adrnin-
isiration
of
an
uruichulin
ester-ase.
lnununulogicaltrcatment
inc hrdcs
the administrution
of
pred
nisulnne
or
aza
Ihinprine
(Chapter
43). PIas-
mapheresix. in which blond is removed and
the
cells
returned. may
improve
motor
function,
presumably

by
reducing
the level
of
immune
complexes,
Thymectomy
may be
curative
.
Presynaptic
agents
Drugs
lnhibiting acetylcholine
relea
se
Botulinum toxin is
produced
by Clostridium
hOllllil1l1111
(an anaerobic
bacillus,
sec
Chapter
37). The
exotoxin
is ext raordinarily potent and
prevents
acetylcholine
release by

enz
ymutically
cleaving
the proteins
required for
docking
of
vesicles within the presynaptic- membrane. C.
hotutinum
is very rarely responsible for serious food poisoning in which
the victims exhibit progressive
paruxymparhctic
and
motor
paralysis.
lIolulinum
luxin
type
A is used in the treatment
of
certain dystonius.
such as
blepharospasm
txpavmodic eye
closure)
and hemifacial
spasm.
lnthcse
conditions.
low

doses
of
toxin are
injected
into the
appropriate
muscle
to produce paralysis that persists for about 12 weeks.
Aminogtvcosidc l/1l/ihio/i
I'I
(e.g.
gentamicin)
may
cause
neuromus-
cular
blockade by inhibiting the
calcium
influx required for exocyrcs!s.
This
unwanted
effect uxuully
occurs
only as the result
of
an interaction
with
neuromuscular
blockers. Myasthenia gravis may be
exaccrbmcd.

Pcntamcricnicotinic rcc
l."
plors aho
,,.,;
cur in autonomic' ganglia ;lndthe hrain.
TIICY
havc
VUri,lnl"
of
th~
0
and P·'llbunir :lIld adiffcrcm
pharmac"to~
)'.
Comp
etitive
neuromu
scular
blocki
ng
d
ru
gs
In general. the competitive neuromuscularblocking drugs arc bulky, rigid
molecules and most
haw
twoquaternary
N atoms.
Neuromuscular

block-
ing
drugs
art"given by intravenous injection and are distributed in the
exuacellulnrtluid. They
do not pa.ssthe blood
-brain
burrier or the placenta,
The
choice
of
,I
particular
drug
is
often
determined
by the vide-effects
produced.
These
include histamine release. vagal blockade, ganglion
blockade and sympathomimetic actions.
The
onset of action and the dura-
tion of action
of
neuromuscular blockingdrugsdepend onthe dose. but also
on other factors (e.g. prior usc
of
suxamcrhonium, anaesthetic agent used).

Tubocu
rarine
was introduced in 1942 bur is no longer used.
C
auamine
docs nut block
ganglia
or release histamine hut causes
undevirable tachyc
ard
ia by
blocking
the M
2
-musGlrinic
receptors.
the
subtype
of
ucerylcholine receptor that
predominates
in the heart
(Chapter
7).lt
i, rarely used.
Pa
nc
uronlum
is an uminoxtcroid
neuromuscular

blocking drug with a
relatively long
dura
tion
of
action. It
docs
nor block ganglia or cause
histamine
release.
However.
it has a dose-related
atropine
-like effect on
the heart that can produce tachycardia.
vec
urcnlum
and
au-acurtum. These arc
commonly
used agents.
Vecuronium
has no
cardiovascular
effects. It depends on hepatic
inactivation
and recovery can occurwithin
~O-30
minutes,
making

it an
attractive
drug for
short
procedures
. Atracuriurn has a duration
of
action
of
15
-30
minutes. It is
only
stable
when
kept
cold
and at Inw pH. At
body pl l
and
temperature
it
decomposes
spontaneously in
plasma
and therefore does not
depend
on renal or hepatic function for its
elimination. It i., the
drug

of
choice
in patients with severe renal
or
hepatic disease.
Auucurium
may
cause
histamine release with flushing
and
hypotension.
Roc
uronium
has an intermediate
duration
of
action
or
about 30
minutes but with a rapid
onset
of
action (1-2
minutest
comparable
to
that nf
suxurncthunium (
1-
1.5 minutes). It is reported to have no

cardiovascular effects.
De
polariz
ing
neur
om
uscu
lar
b
lo
ckin
g
dru
gs
Suxamcrho
ntu
r n (succinylcholine) is used because
of
its rapid onset
and very short
duration
of
action
(3-7
minutes).
The drug is
normally
hydrolysed
rapidly by
plasma

pseudocholinesterase.
but a few people
inherit un
atypical
torm
of
the
enzyme
and in such
individual,
the neu-
romuscular
block may last for
hOUN.
Suxamethonium
dcpolarizes the
cndptatc
and. because the drug
does
not
dissociate
rapidly from the
receptors.
a
prolonged
receptor
acrivuuon
is
produced
. The resulting

endplate
depolarization initially
causes
a brief train
01'
muscle action
potentials and muscle-fibre twitches.
Neuromuscular
block then
occurs
as a result
of
several factors which include:
(i)
inactivation
of
the voltage-
scnslttvc Na"
channels
in the
surrounding
muscle
-fibre
membrane.
so
that action
potentials
arc no
longer
generated:

and (ii)
transformauon
of
the activated receptors to a
'desensitized'
state, unresponsive tu acetyl-
choline.
The
main disadv<tntage of sux<lmethonium is that the initial
asynchro
nous
muscle
-l1bre twitches
cause
damage.
which often results
in
muscle
pains
the nex! day. The
damage
alsn
causes
pot,lssium
release. Repeated dost's
of
suxalllethonium may
cause
bradyCi.lrdia in
the

absence
of
atropine (a musc:trinic effect).
19
7
Autonomic
nervous
system
SYMPA THETIC
SYSTEM
PARASYMPATHETI
C SYSTEM
•

R
~,
:'~
:
~
,,-

I
"C
NC:
o
':::
'''
p
iC:
",:::

p:;:
h''
n
"
~
lI~
- - - -
__
~
r
tea
r
eecr
euc
o
conemcnco of
pupil
accommOt:laUon
far-nea r vision
much
~c
re
tiOl
'l
of wa
tery
eallva
rate and
fora
reduced

l7r'on-chocon
.,;
trietiO
trronchou-cre-tion
Acetylcholinll I
Effe
ct
"
(t)
~Ii
vary
~
Ia
n
d
a
(+) circular muecle
of irie
(
t)
ciliary muscle
(+) Isc ri m
".1
gland
,
,
,
,-
~_

(+) IUrlg airways

-

(-)
he
art
(t)gutw
all
(-)
gut
ephtnc
te
re
mcr
eaee
in
.:
(+)
gut
eecr
et
rcne
mo
ti
lit y and
to
ne
(+) pancreae
Irlc ease irl

exocrine and
endocrirle
ee-vee
e.ecr~n
(-
-)
}
~
(
t)
blad
der
d
etruso
r
mi
ct
urit
ion

,:
(-)
~p
h
inc;
te
r
,
,
.

(t)
ree
tu
m defaecatiorl
,
,
,
.
.
(t)
pel1if;
erection
(cc-relea ee of
rlit-ric oxide)
P
Q!;
t¥
~
lI
o
dc
-e-vee
(-
- - )
,
. -
~
-
.
.

,
,
,
,
-
~"
"
, ,
" '
, ,

',"

" .


"",
~I
iv
a
ry
glands (+)
i><ood
" ,Je.)
Le-)
heart(
+)
gut
wall (
-)

gut
5phinete~
(+)
radial muecle .
of pup il (+)
lung ai rwa y",
(-)
bl.adder •
detruoor
(-)
.

ephincter
(+)
uU:ru e (+)
;'
(
-)
.' "
v99o::lefe
rerls
(+)
,.','
!>emirla!
;'
"
, ,
v
e s

~
l
e 9
(
+
)
, "
, ,
ewest
~
l
ll
rld
5
(t ). ' "
pilomo
to
r
mcecle e (+) -
~
1 dil
ata
t ion of pupil
~
rels><atlon
a
CO
I1t,
raction
- - - -

a cont raCt-ion or }
J3
l re
la><atl
on
(depen
d'.>
on
c
:J:::~:t8")
{
mUfjCsri nic
swea
ti
ng
1
pilocrec
ncn
{hatre
5
tarld
on em
a)
Effllc
ts
tl2 bronchodlla
ta
t ion
0:
5ecretlo

n of t hick
",sliva
0: v
aeccceeretct.icn
1
~
2
v
a~illltatiO
n
J
Ii;
rate
and force
increa!>ed
~
/
Jl
l
secreaee
In
a
motility
and
tone
gly~"noly5i'.>
}
glu
CO
r1

eog
el1
csis
(
g
l
uco~e
rereeee
i
nto
blood)
(0ncr. in
huma"
~)
Note: (+) '" = iUltiOl'l
(
-)
=
irlh;!>;tion
In
the
!lympat.het.k:
s~tem
(+) and (
-)
generallyC01'Te.:;!'O"d
to
« ·and Il.r
eccpto
r'!j

,
~peGti
"eIy
Many systcms of the hod)' te.g. digestion. circ ulation} are controlled
autom atically hy the au t
onomic
nervou
s sys tem (and the
cudocnne
sys-
tem ). Com
rotor
the aut
onomi
c ner vous sys tem often involves nega tive
f
eedb
ack and there are man y afferent (sensory) fibres thai carry inlortna-
tion 10 ce ntres in the h
ypo
th
ala
mu s
and
med uttc.
These
centres control
the outflow of the autonomic ne
rvou
s

sys
tem, which is divided on
anatomical grounds imo IWOmajor pan s: the
s~
m pat hcti c
!>
.
\s
h' m (left)
and the p
aru
sy
mpmh
er ic sv tem (rightl. Many organs arc innervated
by both system
."
which in general have oppm;ing actions. The act ions
of
sympathctic Ileft ) and paravympurhcttc (right) srimularion on Iiiffcr-
en
ttiss
ucv arc indicuted in the inner columns and the resulting effects on
different organs '
Ire
show n in the outer
co
lumns .
The sympathetic nerves (Id l.

l leave the thoracolumbar region

ofth
e spinal cord{T I- L
]J,
md synapse either inthe
par
avertebral ga
llJ.:
lia
(0
)or in the pr
ever
t
ebrat
ga n
J.:
lia
Ie)
and plexuses in the abdomi nal
cavity. Postganglionic non-myelinated nerve fibres (I
o:
fl, - - _.) arising
fmm ncurone s in
the
ganglia innervate
mu
st
Or}!:
;
IO
S

of
the body (left).
111C tran
xmlncr
substance released at s
ymp
athetic nerve endings is
nor
eplnephr
me (noradrenaline; lop lefl). lnactivauon of this transmitter
occurs
largely by rcuptake
intoth
e nerve terminals, Some preganglionic
sym pathetic tibres pass directly 10 the adrenal m
edulla
Ill)
that can
release e
pine
phr'Ine Iudrcnnlincl into rhe circ ul.nion. Norepinephrine
and epinephrine
pro
du
ce their act ions on effector organs by acting on
U',
~
I
'
or P1-adrelllll'eptor:\tcxtrcmcl

cru
2n
In the parasympathetic
system.the
preganglionic fibres tright.
__
)
lean ' the central nervou system via the
cra
nial nerves
tc-
pcctc tty III.
VII , IX and XI and the
unrd
and f
ourt
h acr:ll spinal r
oo
ts.
The
y
often
travel much furth
er
than sympathetic fihres bef
ore
synapsing in gun-
gfia (
e)
thar ar

t."
often in the tissu e
ih
el f (righ tl.
The n
erv
e en
dings
of the J'Kl\tgang lionic
para
v
ymp
athcric fibres
(right,
, ) release :
:l' I
~
k
h
lll
i
ne
(lop ri
ghu
, which prod uce its
action on the effe
ctor
organ<. (right) by
artjvarin
g mus

curm
ic rec
cp
-
tors, Acetylcholine
released at ynapscs is inacti
vated
by the enzyme
ace
tylc
holinesterase .
All the pregangfiomc nerve
Iihres tsyrnpathctic and parasymparh-
E
pme
phrtne
(<Il
ln'
lIu
!i
ne) mimics most sympathetic
eff
ect , i.e. it is a
sympathomimetic uge/l/ (Chapter 9), Ellio t suggested in 1
90-1
that
adrenaline was lhe syrnpmhe
nc
tran mine r suh r
anee.

hut Dale pointed
out in
1910 that IlOrl/llr('//(/!im' mimicked syrnpurhetic nerve stimula-
tion
more closely.
E
ffe<:
1s
uf
sympat hctlc stim ula tio n
These (Ire most eu ily
remember
ed by thinking uf what
dll
ll1ges in the
body arc approp riate in the '[ri,lIhtorflight reaction', Note which of the
following
effec
ts ;ITC
excita
tory and whi ch arc inhibitory.
I Pupillary dilat
ation
(more light reaches the retina).
2:
Bronchiolar dilatation rfacituatcs increased ventilation).
3 Hea rt rate and force
<Ire
incre ased; blood pre ure rises (mo re hlood
for

increased activity
of
kelet
almu
scles-crunning'].
-' Va o
consm
cnon
in skin and viscera and vasod il
.uauon
in skele tal
muscles
(appropriate r
edismbuuun
of
blood to muscles),
S To provide e xtra energy, glycogcnotysi is slimulatcd and the blo
od
glucose level tncrea

. The gas trointestinal tract and urinary bladd
er
relax.
Adr
enec
epturs
are di vided ioto two main type : a-receptors med iate
the excilatnry
ef
fCl'ls o f sympathurn imct ie amin.·s, while th

eir
inhi h-
itory
cf
feeh are gl'ner
<i
Jly medillled by /J· n't"t'!Jlors
(cxce
ptions arc
the smooth muscl e
of the gut. wl1l're a -stirnulatinn is inhihito
T)'.
ami
lhe heart,
wher
e
f}

timul
at ion is exci
talo
ry). Rcspon ses medi at
ed!:o
y
{l
-
and
~
1\.
'C

eplo",
co
m he di tingui hed by:
(i)
phentolamine and
prop
ra·
nolo l.
which ,I'dec/h'dy block u - and
f}
-receIlIO
TS
, re pectively: ,ml!
(ii) hy lhe relative pot
encie
s. un
differ
cnt li ues.
of
nllrt
'p
inephrinc
(N
El.l'
pinephrine
(E)
and isoprenaline ( I I, The o r
der
of potent-y is l" E
> E > I where excitatory (

a)
respo
nses are examinffi, hut fo r inhibitory
(13) re ponses this ord er is reversed (I » E > NE ).
~Adr
cnu
el.'
ptu
r
s
are nOI
homo
gencou , . For example,
norep
ine-
phri ne
is an effect ive slimulllnt
of
ca r
diac
p
.rcce
pt
ol"1;,
hUI has lillIe
or no acl ion on lhe
~
-
r~'CC
p

l
o
rs.
l1
R'diating vaslxtilalalion. On Ihe bas is
of
Ihe type of
diff
t' rt'nthtl sensitivily they e xhi
1"li
l to drugs,
f}
-receplurs
are dividl'd into two types: PI(he,l
n,
inte tinal smooth muscle) and
f}
2
(bronchial. vasc ular and
U1
eri
llC
SlIlU
Olh musele).
a .Ad
rr
llUcl'ptors h;!ve been di
vided
inlo two c1a ses, origin ally
dependin

g on whelh
er
their
IO~'al
i\l1l
W
llS
po tsynaptic
(U
I)
or
presynap
-
tic {U l l. Slimul
alio
n of the pre )'nuplic a
2
-rcl'cplors by syn aptica lly
relea
Sl.
'lI nnrepillCphrine reduce fun her lransmiller release (negative
f
ccdh
al'k ), Postsyna ptic (ll-reel
'ptor
s
occ
ur in a few tissues,
e.g
. br.lin.

vascular smooth
mu cle (but mainly u
l
).
Act'
l~
khu
linl'
:
\
l
'
l' t
~
khnl
inc is the
t
nm
~m
ille
r
suhsta nce released by the following.
eric. _ _ 1
are myelin ated and release acetylcholine trom the nerve
rcn
nin
als : the acetylcholine
depo
larize the gangl ionic n
eur

one by
activating
niconmc
rece
pto
rs.
A small proportion of
autonomi
c nerve do nlll release eithcr
acetylcholine
or
nor
epinephrine
. For exam ple. the ave
mo
u nerves
rel
ea
se
nun
c oxi de (N
O)
in lhe penis. Thi s relaxes the smoo lh mu scle
of
the co
rpo
ra cavem
osa
(via cycl ic guanos ine
-J.5-

rnollophosphate
(cG MPl,
Chapter 16) allowing expansion
of
the lacunar space v and
erectio
n.
Si
ldl
'lm lil, use d in male sexual dy
sf
un
ction
, inhibits phos-
phodie
t
er
asc type 5 and, b)' tncrce ing the conce
nua
uoo
of l-GMP,
f
ad
litah.· erection.
I All
pregan
glion
ic autnrunnic
nerve
s rl.e. both sympathetic and

para ympathcricI.
2 Poslgan gl ionic parasymparheuc IlCrvCS.
.1 Som e post ganglionic sym pathetic n
er
ves ti.c. th
ermorc
guhuory
s
WC:
L1
glands and kclctal muscle vaso
di
lator fibres),
,J Nerve to adrenal m
edu
lla,
S
Som
atic
moto
r ne rves 10 skeletal muscle endplutcs (Ch apter 61,
(,
Som
e ncuroucs in the central nervous system (
Chapte
r 22).
A
c
t'
l

~
lchnlme recept
ors
(chlilinuccplurs) arc di vided into nicotinic
and muscarinic ubrype s
(o
riginally det
ermine
d by
meas
uring the
sens
iuvity of various tissues 10 the drugs nicotine and muscarine,
respectiv ely ).
M UJ('urinic receptors. Accr
ykhclin
e released at the nerve terminals
of
postganglion ic
para
s
ympat
hetic fi"res acts on mu
scarinic
rece ptors
an d
can
heblocked selectively hy atropine. Five subtypes ofmu scarinic
rec
eptor

exist
. three of which have been well charact
cnz
cd: M r' M
2
and
~
1
.
l
'
M
t
-
f'Cl.
"epto
l"1;
{lccur illthe
brain
and gas lriCparietalt1:
11
,
M
~ - TCl "
'Plnr
s
in tbc heart and Mr-rece
pto
rv in moo th
mu

scle
and glands.
EXCCP
I
for pi
renxepm
e.

hich selectively bloc j, Mj"reCCPlOrs (Chapter 12),
din
k-all y useful muscarinic ugonists and ,mlagonists show lillie
or
nil
selectivity for
the different uhtypc s of muscarinic rece
ptor
.
Ni""fi"i
c
ren
·f'f.wS occ ur in autonomic ganglia and in the ;Klrcnal
m
edulla
, where the effeets of ,ll'l'tylcltolinc (
Ill
nicotine )can be
hlod
l'd
se lectivcl)' with
heXlllnethonilllll.The nil-olin ic reC

ephlr
Slllthe
~k e
kt;i1
tnusek neuromuscular
jun
ction are not bkll'ked by
h<.
'xarnethoni
um,
hut
arc
No
d cd by tuhoc
ur
.lrine ,
Thu
s, recepto
l"1;
at ganglia and neuromus-
cular
jurll'tions are
diff
erent, although hoth types arc timulated hy
nicoline and ther
efore
called nicotinic.
Actions
vj
flcety

ll'lwli
flt'

W/f,l'(
·<Jr
inic e1f{'ff,1 are mainly p:lra, ymp,llhOlnimet ic (except swe,uing
and vasodilatation), ,md io ge neral arc lh
:
opJ'Kl
site
of
thosc cau.,ed by
sy
mpat
hetie slimulati'ffi. Musearinic
ef
fe
cls
in
dude
: con lriclion o r lhc
JlI.lpil.
a
~'C
o111m(l
•.
bli
on for ncar vision
(Cha
pler

lU)
,
pmf
u : walery sal-
ivalion. bronchiolar con trictil,n , bronchll
scl
'retion,
hypo
lension (,lS a
result of bradycardia and vasod ilatation), an inl'Tease in g,."
tm
intestinal
mOlility
and sce retion,
co
ntral'lion or the urin ary bl;ldd
cr
and swe:lling.
Nin.
rinic
l'jfl'l"/
.I in
dude
slirllula
tio
n
of
all autonomic gllllg!ia. Ilow-
:v
er

, lhl' action (JfIKctylcholinc nn ganglia is relatiVely weak ellrnp:rn'd
with it
ef
fl'el on muscarinic
fI.'Cc
pto
rs.
aml 11 para.' ymp,llh

tie cfli:cts
predom inate.
The
nico
tinic aclilln
of
acetylcholine on lhe
sym
palhl'lic
system
",
Ill
be denlllll
.'-lr:ll
ed , fllr example, un cat blllllll pre sure, b)'
hlorki
ng its musC:lrinic actions wilh atrnpirll'. High inlnl\'l'nous doses
of
al'ely
kho
line then cau a ri e in blotlllpr.:ssure. hccau sc stimulation

of lhe
~
y
m
pa
l
h e
l
i
c
gang lia and adrenal medulla now results in v
asoco
n-
slricti'
l11
and lad tycardia.
"
8
Autonomic
drugs
acting
at
cholinergic
synapses
ICI1olinomimol'tlc5 I
1 0 $"'3
1;
0" I
,
,

,
,
,
,
,
,
,
,
r
,
,
,
,
Pree
a"
'3110n
ic
5ymp
at
hetlc
" .
~
,
.
.
,
, '
, '
,.
, '

,
.
,
,
,
,
,
Nicot inic 8goni
et
s
,
(ganglion
,
,
etl
mulant e)
• • • • - 1
.
"i
ro
t !ne



,
,
carbachol
(Wl:l\~)
,
,

a
nti
c
h
o
l i
rP
e
!>
te
r
s
~
e
,
(weak)
,
,
,
.
.
Ga nglion
I:>
lockeNl
.
h~m
e th
on
iu
m

trimet.8pha
n
exceee
nicot
ine
(depol
ar
izing blo
d)
MUl!lcarini c
.;;:-<"
.
ant.agoniet e
at.ropine
byc
ecne
ipr
a:trOplum
t.ropicamide
benz
atropin
e
cth
ere
,
,
,
,
,
,

,
,
,
,
f'~8,.,~
lionic
P"r
" ymp
"t
h"tJc
""

"






'.
"
"
"
"
"
"
'.
;'
;\':
"

"
" .
_ - r' :: ·.·.c·.·
- ,' -

,
,
,
,
IGa"'llionI
'"
,
,
,
edrophonium
neo~tl
gmjne
di
t>
t lgmine
pyrido
fit
l'3mine
(organoph~phoru5
compoundS)
Ant
i-
cholln eo
te
raeeo

C;3
rbachol
b
et
M nechol
pilocarpine
MUllc
ari
nlc
iii on
ill
tll
Acetylcholine Tek
o
lsl'lI
Inun
rhc tcrminalv of postgangliunic purasym-
p
atbcnc
nerves (h:ft . D ) pro
du
ces ih m,:lions on
vano
u-,

tfcctor
organs by activating mu
c:
ar
inic rec

ept
or
s ( 0 ). The
ettcct
v
of
acctyh-hnlinc an: usually excitatory. b
uran
impo
rtant exception is rhc
heart.
which receive inhibitory cholinergic tlbres t'W11l the vagus
(e h.lr lcr
171. Drugs that
mimic
llll'
cncce
,
Ill"
acetylcholine arc called
l
'hu
linom
inll'l k
!'o
and can IX'
divide
d int
otw
o

grou
p~
:
• drugs Ihal
,WI
directly
"11
~C
p
h
ll
"
<
nkolin
k nndmU"l'a
rink
a~"ni
~
l
~
)
:
and
•
anl
k
hl) lin
l
·
sl

t'
r
a
"l.
~
.
which inhihil ac
et
ylcholinesterase. and sll act
indirectly hy ;llluw ing ac
etylcholine
10 u
ccumnlatc
in the synapse
and
prod uce us effects.
:\IU
S4.'"
;Irink
3~
l
lll
i
s
h
(lo
p
kfll
have
kill

U'>eS
. hUI piluc
arp
me (as
cyc
drops) is IIM.' d tu redu ce innao
culnr
prcvsure in pariem s with
glauc
oma
(Chuprer 10). C:l rh;lchu] and
hethun
e
chul
are used 10
vrimuf utc
lhl' bladder in urinary retention under conditions where Ihere
is no ubvtrucrion III Ihe bladder nutle t tc.g. in ncurologtcul
di~
e3~e
or
postopcrat ivety l.
Anlichlll
in
t<St
c
nl
w s
(bottom
left) have rcfauvety little c

ttec
t ,II
ganglia and arc use d
mainly fur their nicotinic enCl
'"
on lhe
nL
'uroT11US
'
cular junction. They arc used in lhc l
Tt'
;Llnll'nl
of
myas thenia
gra
vis and
to reverse the
ct
tect-, of r ompctitivc muscle relaxants used during
surgeT)' (ChaplCr 6 ).
.\lu
"l.'
3r
ink
lI
n
t
a
~
onh

ls
(bottom
middl(') block (he effe cts of ac etyl-
choline released from
[-"lsl
gan
glio
nic paruxympathctic nerve r
emunal
s.
The ir
elTec's can. in gene ral. he worked nut by ex
.unma
tion
ofl
hc figure
in Chapter 7.
However, parasympathetic effect
or
organs vury in thei r
w nsilivily In the hlocking
effe
ct
of
aruagonistv. Secretions of the sali v-
ary. bronchial
um
l swear glalH.b are movt Sl'n silive to blockade . Higher
doses
of

umagonist dilate lht: pupils. paralyse accornrnodution and
pro
du
ce tach ycardia by blocking vaga l
tone
in the heart. Still higher
du,,<,:s
inhibit paravympat hcnc control o f the gastroiruesrin
ultruc
t and
bteooer. Gastric acid secretion is mosl rcvi-aaruto hlockade
\C
h;lpt

r 12 ).
A
tr
opine.
h
~"
n
'
.
dn
c
( copolamin
cl
or ruher a
ntago
nisrv arc:used:

1 in anaesthesia In h
lo<:
k
vaga
l slowing of lhe hcart
al1<
l 10 inhibit
bronchial seere
non:
2 to reduce imcstinul spasm in, for e
xample.
irritable
bow
el syndrome
(Chapter 13);
.~
in Par kinson 's di
SC:
,I
SC:
te.g. benzatropine.
Cba
prcr 26 ):
Ch
olint'rj!,ic nerve te
rminals
in the autonomic nervou s system vynth c-
size. store and retca se ace
tylc
holine inessentially the

same
way as
anh
e
neurom
uscular junction (Chapler 6 ). Ace tylc holinester
a-e
io;
h
ound
to
both the pre- and
pmt
synapt
ic mcmbranes.
Cholinomimetlcs
(;a
n
~
l
io
n
stimulant
s
These have wi
desprea
d actions
beca
usc they stim ulate nicotinic reccp-
tors on both parus y

mpathc
uc and vymp
amctic
ganglionic neuroncs.
Sympathetic effectx include vasoc
ons
triction. t chycardia and hyper-
tension. Par axymp thctic effects include i
n<:
rea't
-u motility of the gut and
in
creased
sa livary and bronchial sec retion. They have no clinica l uses.
Mu
, c
arini
c IIAlm isls
These
direc
tly ucuvate rnuccarimc rece ptors usually produc ing exclra-
tory effects. An
important
exc
eption is the heart. here activation nf the
predom inant ly Mz
·f<.'Cc
ptO
I'1\
has inhibitory effects on the rate and force

of (atrial] contraction. The M
2~
r
e
c
e
p
t
o
r s
are negativ
ely
cou plcd by a G ·
protein (G I) to u
dcnyly
l cyc lase. which explai
n,
the negalive ino
tTll
pic
eff
ec
t of ACh. Suhuni s il3y)o rGI dire, lly Incre
a,e
K + cnnduc
I1
\llt'C' in
lh.: h
eart
c1lusing hy

perp
nJarization nd hradycardia (Chaptcr 17).
ACh
, limulales glandu
l1
,r
","'Cre
tion and
C;I
U

Sconlraclinn of mooth mu cle
by ac tiva ting M 1·ft.'Ceplol'i. whi ch ar<:cnu
pkd
to lhe formalion of InsPI
and
d
ia
c
yl
g
l
y
c ~rol
(Chapt
er
1). In
'P
I
incre " >e, cy t

o,o
lic Ca
z
+.
t
h u~
trigg ering mU."Cle
CO
lltmction
or
glar
l<
fular ecrclion, An intrave nous
Injeclioll
nf AC h CH
U.
-es va,odi lalalion in
dir
ectJy by rele asing nitric
oxide (NO) fmm
va,c
ular endoth
di
,lI ce ll, (Chaptcr 16). Ho wcvcr,
m
n'
l
hlood
ves ·l have no para"ym p;tlhelic innervation and so the
p

hysio
logical function o f va cular lIIu
o;c
arinic recept ors i, unccrtain .
C h nli
lle
es
le
rs
C a rbat'hol ami hl'l
hanl
'(·hol arc tjualem ,try l·ompounds Ih11\
do
not
penetrate thc hl
<xM.!
-hra
in bam er. Thd r actions arc much more pro -
longcd than tho, e of acety lcholine,
bccOl
use they are not hydroly ·d by
chuline terase,
Pil
ocarp
inl' po""cs'\Cs a h:rtiary N '110m,

hich
co
nfen; increa

d
lipid
soluhility.
This
enables lhe drug tn r<:netrate lhe
co
rnea rc,ldiJy
when
applied locally. and COlcr lhe
brJin
whcn gi\'c n s)'stcmically.
,\
nt il
'hol
inc
,l
cra
,
c,
n lt'
>;e
are indi re, tly at·ting cho linomimet ics. The commonly USl'd anti-
l'ho!i
nc,
tera e drugs are 4umcmary t'nrnpouluh that do mIt p;tss the
hltx
ld-b
rain oa
rril-°
r alld

have
neg ligible
"n
traJ
ef
fOXh
. They are
poo
rly
aoso
rbed orally. l
·h,

"l
i
~lI1in
e
(eserine) is a tertiary amine ,Ind
i,
much more lipid suluh le. It
io;
well
ahso
rbed aftcr
ora
l or
lr.)(:
al a
dminis-
tratil,n (e.g. ,IScyt-d rops) and p,I"Sl'Sinl

lll
lu: hrain.
'
l
~
h
a n
is
m o r
al
'lion
Inilially. ace ty lcholine binds to the aClivc , il':
of
the e"terase and i,
.&
10I'rcve nt motion sid dless thyoscinc. Chapter 30 );
5 tn dilatt
'th
c pu
pilfo
rop hthahuologjcal exarnimuion re.g. tr opicamide j
or
to
paralyse
the ciliary musclc t'Chuprcr 101: and
II as a bronc hodilator in asthma ti prarropium.
Chapter
I I).
Transmission at auton
omic

ganglia (
(:)
ca
n
ho:
slimulaled h)'
nicotinic
agtln
is
t.~
ttop middle)
or
bloc
ked by dru gs thut ,
ICt
specifically
on the g,
lI1g
lionic neurone nicotinic reccpro
r/ionophor
c
(midd
le),
Nicotinic
agn
ni.,ts arc
of
no clinical usc hut ganglion
blo
ck

crs have a
limited u
sc:
in anaesthesia.
hydroly

d. pro
du
cing free choline and acetylutcd enzyme. In a sec
ond
step. the cov alentac
et
yl-enzyme
bond is vpfit with the
addition
of
water.
Ed
ruphnnlum
is the main example
of
a reversible un
nc
hotin
cstc rasc. It
binds
hy ulcctrosuuic force"
tuthc
active site of the e11lYI
11e

, IIdocs not
form covalent bond s
wnh
the
enzyme
and xo is very short acting (2- 1()
minutes). Th e carbanuue eslers (e.g ,
l
ll"o
,t
i
~lllill
l'
.
II,
ridl
l!>
liJ!llIine)
unde r
go
the same two-step P
f<
x:e
o;s
a,
acct
ykholin
c. except that the
breakdown of the carbamylascd
enzy

me is much s
lower
(30
numne
v
to
6 hours) .
Org
anop h
osp
horus agents. (e.g. l't.'u
lh
io
pa
le ) result in a
phos
phoryla
ted enzyme active sill'. The cov alent phovphorus enzymc
bond is very stable and the e
nzyme
is
inactiva
ted for hundreds
of
h
our
s,
For rhi-, rca-
on,
the organophosphorus

"'O
l11pO
l
l11
<1
s are r
ef
erred
to as
irrev
er
sible auticholincstcnescs. They are
extr
emely rox ie and used as
insectic ides Iparat hion. mala th
io
n ) and chemica l w
arf
are:agent"
Th
e erTl'l
·"
or
an
tk
hu
lin'-"'It'
ruo;eo;
arc generally vimllar 10 mo-e
produced hy

the dire ctly acting
me
-canmc
agllll
io;
t,. but, in addi tion .
tran smisvion
al thc neuromuscular junction is potentiated. The choline-
«e
rase inhibitors produce less vasodilatation than the direc tly acting
ago nists
~
C
,
IlJ
se
they can only act on lhe (fl'W) ve""
ds
p
o
~
se
ss
in
g
cholinergic innervation.
Abo
, stimulation
of
sy

mp
athetic g
Ol
nglia may
oppose th
va,
odi la
tor
ef
kcls
of
the drug. On ly large tox ic do es
of
3m icho lincst
cr
J.
SC:
prod uce marked
bmd
ycardia and hyp()te
n,ion.
Tox ic
dllo;eo;
initially
C;l
U e
signs of eXlreme mu carinic stimulation:
mi
mi
, . salivation. , wcaling. hrOiKhial

co
nstrictinn. hronrh o"ecretion.
vomiting and dia rrhoea. Excessivc stimulation
of
nicoti nic rece ptors
may C,
lUS
C depol arizing ncummu ' l'u lar blt
X"kar.
!t If th drug is lipid
soluole (e.g. phY
'o
sligmine. orgallophospho
ru,
com
p<
lun
d'l.
cOlwul-
sinns.
Com1
1and respiralOr)' arrc sl may occ ur. Strong nud eophile, (e.g.
prali
dn,
inu: ) can spJit the p
h<
phoru s- enzyme bond initially formed
hy orga
nnpho
"p

horus clmlpo unds and
'rege
ne
mtc'
thc c
n/y
me. Later
lhis ht.
"C
1H1
lCSimpo
o;s
iblt' ht ·a
u"·
a p
nx.""
of 'age i
ng'
streng the
n,
lhe
phosphuru, enl yme oond.
Cholinergic
receptor
anlagonists
Ga
n
~
li
o

n
hl ud ,
er
s
These
ca
u'\C
hypo
le
n,
ion. mydriasis, dry mouth. anhidmsi, .
co
nstipa-
tion . urinary
retenl ion and imp<,lence. Tri metaphan is u
",d
to
pT<Xlu
ce
cOlllru
lk
-J hypulen, ion d uring ce
nain
surg ical
pru
<.
"d
ures.
l\Iu
,{

'arinil-
;
l
n
l
a
~
l)
n
is
ls
A1rulline o< curs in deadly nighl
,ha
.1c(Atropa
hd
i
m/
olll"').1l
i
~
a weak
ce
11l
rJI stimulant pcciaJly un thc vagal nucleus. and low dnses
often
ca
us<:
hrady
cardi
a. Higher do

s cuu e tac
hyca
rdia.
lI,
u,
cin
c
(S/'Ol}(l/
-
amilli')
is more sc:dalive lhan atw pinc and often prtlduc.:s
d
ro\l,
~ill
e
",
and
amn
e, ill. T\)'lic
do
s<:
,
of
txlth dru gs ca
us<:
exci
temt·nl. agi la
tio
n.

hallu"'inatinn and coma. Thl"
\."f
fect, uf musc<trinic anlagon isl" can be
work ed nul hy
tudying lhc ligurl' in Chapter 7. n le sludell! should
undt'rstand why these
d
ru
g
~
produ
ce
dila
ted pupils. olurred visidh , dry
mouth.
co
n,t
ipation and diflit'uhy with micturition .
23
9
Drugs
acting
on
the
sympathetic
system
Nor
adre01U~
tC
Mrve

termin,,1
• Partial
a<\ol1i,.;1
SCIivlly
t
MOIJlllpid
"",lut>l~
It
Lea,.;llipid
ooIu~
Adrenergic
neuro ne
blockertt
. •
r~rpi",,':
"
l~
i""
guanethidine
.•
W;t.hanldlne
Adrenoce
pto
r
antago
nitttlll
a
·
~
OC

" E
R5
U,
/U
2
phenoKYVcnZSmine
phentolamine


a ,
,
••. prazooin
1l-8L
OC
" ER5
Il
,
/IS
.:
prop nolol t
naaclcl
tt
t imolol t
oKprenololt ·
pinaolo]"
ca
rve-d
ilol
I
~

(card
i05elective)
me:toprolol t
aU
nolol
tt
acebutolol'
-'

Pff:VI'",I~
:::

;;wr~"
:::
,:'
\)'-,-/'
"

" "
,)/,'\
,"
'::"
Pff:V/:rlrIJ
r/:lca~
D~a"'
l
naud
mM-a"olite

DI~ceNE
NE
NE
"
.,'.

'.~



'P
~
'.,.,
~
~~~":"":::::::
Inoctl~
.st ion
Mffii~lteg,'
::;
'.
".',
5y
m
patho
mj
m~
lcl!l
Indl
rect-Iyactlng
"',

e:
phedrirle
amfetamine

(tyramine)
cccaloe

-
Direct l
yac
tl
ne
U
-
AGO
~
j
S
T
5
u
,l
u
~
n
or
epine
phr
ine
epinephrine

a,
clonidine
u-meth yl-
rlOrepinephrine
"
phenylephrine
methoxamine
1'
''
600
15 [5
1i,/J3
2
epinephrine
ioopreMSliM

~.~

P

5al~utamol
u rou
ta
line
p,
norepinephrtrte
dolnJtamine
The sympathe tic nervous system is important in regulating nrgml' such
as
the heart and pcriphcrulvascul.nurc (Chapler, 15

an.llll
).Tlu-trans-
muter
released from sym pathetic nerve enuill
ll-s
is
nur
e
pin
ephrfne
(
I\
t:l (noradrenaline.
c:»
bur. in response to some forms of stress.
epilll'p hrine (adre
naline.
is
also
released Irotu the ndrcnalmedullu.
The-e carecholamines
a TC inactivated mai nly by reup
tak
e (

J.
S) llIpa
lhm
ni melics
Od"T)

arc drugs uuu partially or co mpletely
mimi c the actions of norepinephrine and epinephrine. '1
11<
:y Jcl e ithe r
directly on (1 - .mdlor
IL
ldreno
ceplor
s (left. open column) or i
ndin
·ctlJ
on the precynuptic terminals (lop lefl.
,halkd
/. usually by cauving the
release of norepinephrine (
c:>
l. TIll' effcct-,
of
adrcnoc
cptnr
srimulu-
tion
can be
we
n in the tigure in
Chapter
7.
p1-,
\dn
'/lll('epl

"r
ugoni

's cause bronchial dilatuuon and arc used in
the treatment of
asthma
(Chapter II ). They arc
aho
used 10relax uter -
ine muscle in an auem pr to prevent pretcrm labour. P.
-Adr
cn' l('
t'plor
al:onisb (dobuturniucj arc s
ome
times used to stim ulate Ihe force
of
heart c
omra
c
uon
in severe Im"'
-OUII'UI
heart failure (Chapter III).
a
l
-A~(ln
i
sh
re.g.

ph(,l1~
le
phri
nl' )arc used a-s mydriatic (Chapter 10)
<t
nd in man y popula r deccngcvtunt preparations.
a
l
-A~o
n
i
sb
,
notably
c1nn idinl' and meth
jldnp
u (which (ll'l" utter
ib
conversion 10 u-
mcrhytnorepinephnnc. a false transmitter). are centrally acting hypo-
tc
ncivc
drugs (Chaple r 15),
Symp;lthnmimclk amine" that <letmainly by causing
nnr
el'i
nl'
phr
int'
r

elease
(c.g. amfe la mine )have the a
iu
!selectivity ornorepinephrine,
Ep
hed
rm e, in addition
In
causing nor
epin
ephrine
release. a
bo
has a
direct
action. lis effects resemble those of epinephrine. hut
l
a
~t
much
longl'r,
Ephed rine is a mild central stimulant, hut amfetamine,
~
'hk
h
enters
thl':
brain more readily,
hasa
much greater stimulant effect on mood

and al
crme
xs and a depressant effect on appetite. Amfetami ne and vim-
ilar drugs have a high a
buse
potential and arc rare ly used (
Chap
ter 3 1).
~
Adr
enn
t
'
t
'pI
Clr
anl
~ l
~uni
sl
s
(fl-hlut'k
ers)
(bonom
right) are im-
portent
drugs in the treatment (If hypertension lCh apter 15), angina
IChapter 16), cardiac
arr
hythmia-, (Chapter 17). heart failure (

Cha
pte r
18) and
glaucoma
(Chapter
10).
a-A
drt
'llucellln r
a
n b
.~u
n
isls
t
a-
R
eu
pla ke of norepinephrine by a high-alfinity tran sport system
(Uptake I) in rh

nerve t
erminals
' recaptures '
mo
st
of
the
transnuucr
and is the main method of t

crminaun
g its effec ts. A simi lar (extrane u-
ronal) transport system \
Uptake 2)eJlists in lhe lissues but is less se fec-
rive and
less easily saturated.
:\Io"
ollmint'
o\
idaw (MAt H and
ca
lec
h
n
l
-
O-
n
l
e
t
h
~
l
l
n
llls
f
e r
a'iC

tCO :\I
T)
are wid
ely
distributed
enz
yme s that cata bolize catechol-
amincs. Inhihition
or MAO and
("0
1\11'
has little potentiating effect on
respon ses to sym parhcnc nerve
stimu
lation
or
in
jec
ted carec
hola
e
unev
(norepin
ephr
ine,
epine
phrine) beca use the
)"
are largely inactivated b)'
reuptakc.

a ,
\dre
ntll.'eplo rs are pos tsynaptic.
Their
activation in
seve
ral
tissues te.g. smooth muscle, salivary
g
l
;l
n
d~)
causes an increase in
inositol
tnsph
ocphare and suhsequcrnly cytosulic calcium tChapter I),
which triggers
muscle cont raction
(excep
t gUI)or glandu lar secre
tio
n,
~
.
(\
d
re
nn
t

'l
' l
l
tnrs
o
ccur
on noradrencrgic nerv e termiuuls. Their
activ urion by norepin
eph
rine inhibits adenylyl cyclase. The
c
O
I1~

quem
fall in cA \ IP cloSt'S
C
a
~
+
chanllCb and diminishes further tr aus
miucr
release,
fl-Ad re
f1
0l:
epl
nr
aelivation results in stimulalion
of

<l
d
n
ylyl
cycla

. incre;lsing the COilversion
or
ATI'
to cAMP, The cAMP aels as
a 'secolul
mc,s
l'nger' coupling Tl'e
epto
r ;lclivation tll
Tl'S
p'
l
n~e,
Sympathomimetic
s
Ind
in'
!'lly a
ctin
J:Sylll p;llhnm i
melics
Ind irel.'
ll)
acti

n~
s.\ mplilho mime lics resemhle the
~
l
nK
'
tu re
of
n
or
epil1
~
'phr
in
c
d OSl'lyl'llough 10 hL'
t
ran
~p'
,ned
by Uptake I intn
",:TV
e
t
enninal
s wherc the)' displace
ve~
ic
u
l<tr

nnrepinl'phrine into the
c)
'loplasm. Sonw of the norepinephriue is nwtahol
il-LxI
by MAO, but
Ihe
remainder
i
~
rd
eased b)' earricr-m dia
t<.x1
tr.msp
on
to a
di
vate
adrenllceptors.
Amfelam ines are resisl<lntto M
AO
.
1llcir
per
iphl'r;ll action s (e.g.
\;lChyc
llTl
lia,
h
Yp'
.'n

l'n~i
lln
)
;md l'l'ntral slimulanl act
iol1
s arl' mainly
eaus
<:
J by catcchnl:lInine
rd
c
a'
c,
I)t
"\
anl
ft'lalllinc and
lIIl'l
h
~l
jlh
t
·ll
i
.
da le are
somet
imes u
loC
d in h

ypcd
i
llt.'
tic ehilt
lr<:
n. Dcllamfetamine ;
u,,
1
IIlfldalin ii may heh.
:nelid
al in
na
r
ct>1ep~y
,
IA.'pendence on
amf
elamilw,
like
dru
g
~
is C0
l1
111
10
11
(Chapter 3 1l.
C
oca

ine , in add ition 10 be ing a loca l
amW~
l
he
lic
\Ch upt r 51, is a
s)
mp,Uhnmimetic
t->ceau
Sl' il inhihils the rl'uplake
of
mm'pilwphr
ine hy
IWTVe
tcnn inals. It has an inlense Cl'nlral stimulant efFel't thut has made
it
a popu l:lr d rug
of
lthu"l' tChaptcr J I).
Uir
ecll
)' :.!'tinJ:
s
~
mp
a
th
umin
ll'lk s
The effec t

of sym pathomimd ic
dru
gs in hum;lns dq".'nds on their
r
e c~pto
r
sped /icity 1.lt antl/nr Ji) and o
nl
he ctlmpens at
"ry
r
etl
e~
c
~
they
c\
'oke.
Epilll.'llh rint' ami n
urt
'pin
eph
rhw arc
des
troyed in Ihe gut ,
1Il
d are
~
h
o

n
lasling when injcl'!etl hcC
HU
SC
of uptak e ;llld m
l.'l<lbnli
sm,
Epi
ne
phri
ne
incr
ca
e
s
Ih
c
blno
d pressure by slimula
ling
th
t.'
rale and
hl d
\t
'
r ~
l
(
mid

dle right )have limited clinical upplicatiuns. Pr
azo-tn
. a
selective Ill -antago nist, is sometimes
used in the treatment u
fhy
perten-
vion.
I·h
en u\
~h
en/
.amin
e
,
an irreversible antagonist, i" used 10 hloc k
the n -effccrs
of
the large ;Illltlunts of catecholarnincs released from
tumours ofthe adrenalmedulla tphaeochromocytonnn.
~1
any u -hlockers
have be
en
(and are Ju

-d in the treatment of peripheral vascular occlus-
ive disease. usually with little success.
,
\

d
r
e
nt
'
r
~
k
neurune-blucklng
d
ru
~
s
(lop right . ,haded) either
depk-te the nerve r
emnn
als of
nore
pinephrine
trcse
rpinej
or
prevent its
release. They were used
a
~
hypotensive
ag~nh
(Chapter 15 ),
force

or
thc he
an
hcal (
13
1
-cfk cls). Stiruulatioe
uf
vascular a -
TL
'C
epIOTS
causes vaso
cons
tncuon
tvisceru, skin) hut
P
~
-stimuratio
n
cause
s
vaso
dila
union (skell'tal muccIc' and the total peripheral resistance may
actuall y
dec rease.
Norepinephrine has
linlc
or

no effec t on the vascular
p
~ -r
Cl
'I
'ptors
and so the
u-
mediated va
scconcmcr
ton is
unoppo
sed . The resulti ng rise
in blood pressure rcncxtvcty
slows the heart . usually overc
oming
the
dire
ct P I-stimulant action on
th~
heart rare.
Epinephrine hy injection has an impo
na
nt use in the treatment of
al1aphylactic
.\hod
; (
Chapter
II ).
j.l-K

ec
epl
nr -w lect
i,
e
dru
~
s
Isopr
en
alin e stimulates all Il-Tcl·eplOrs, increasing the rate and force
of
the heartbeat and
ca
uvlng vas odilutarion. These
e
r
fec
t~
result in a
fall in diastolic and mean arterial pressu re with lillie change in s)'stolic
pressure.
13
:-Ad re nnce
pln
r
lIJ:
lln i
sls
arc relatively selective drugs rl

uu
pro-
duce broncho
ditatanon
al doSl's that cause minimal
ef
fects on the heart .
They
are resi
stantltl
MAO
"luI are proh ahly nl'! taken up into nl'urones.
Thl'ir main use is in thl' trcalnll'1ll
of
asthma (Chapter I I),
Adrenoceptor
antagonists
a-
IUuc ke
rs
a-
lIInd,; t
'r
s reduce aneri
olar
and venous lOne, causing a f;lll in
pcr
iph-
er
<l

l rt:sist:lIu;e and hypotension (Ch,tplcr 15), They
rcwrs
e lhe
pr
e
s~or
cf
fL·I
.'ls of cpinl· phrin heca u

its l}2-med i
aled
vasod ilator effects an:
unopposed hy
(X
·me
diated \,asOl'(lllSlriction and
IhI':
periphcr.tlresist;tnce
fa
ll
~
(epineph rine re
wrsa
ll, tl-BIOl'ken. cau, a r
en
e
Jl
tachycardia.
~

h
k
h
is gre;lll'r with m m
-~IL't
'
l
ive
drugs thai also blt,.
.ok
u 1
-pTC'i
)'naplic
r
cr
er
lnr
~
nil
t
h ~
heart ,
hL-c
au

Ihe augnwnted rel u_se
of
nnTl'pinephrine
.,timulat
<:

s
furth~r
thc ca rdinc
Il
-
r~
!
·
cp
tnr
s.
Pr:lI.n
sin
. a sclective u
l
-
antagonist,
causes
rel;ltively linle tachyc
ardia
.
~
1I
1()c
k
c
r s
fl-
H1
l1t:

kers
vary in their
/iflid
,failih
ili
ty and (',m !io.w ln til';ty.
11
0

-
cver, they all hloek Ilj-rcceplurs and are cqually effective in
fl.'du
cing
bloud pTl'ssure
and preventi ng anginu. Thl' morc lipid-soluhlc
dru g
~
are
nw re rapidly absorhLxll'rom
th•.' gUl,
u
nd
~r
go
mo
re
lin.t
-pa
~ s
hL

' patie
mewbolislll
;md are
mm
e rapidl y eliminated. They are also more likel y
to enter Ihe brain ;md cause centr.tl effects (e.g.
b;K1
dream
s1.Cun!i(Jw!t'l:-
lidly
is onl)' relative lIml diminishes with highl'r dose s. NC\'en hcless,
seleclive l}j-bIIX:kad
e'
l'elllS 10 produce
Ie~
s
peripheral vu
_socon
.stric_
tion
(cold hand s and r<"l,t) and
does
not rcdul'e the response to eJlcn:ise-
indul'ed hYp'lglyeaem ia (sTimul;ltion of gluc
ol'lC
ogenesis in the liver is
metliat<:J by
l}
!
-re

c
~plur
~
l
.
CarJi
o
sd
el'tive dru gs may have
~u
n
ki
l'
nl
fl!-aelh'ily III prct:ipitatl' Sl'\'cre
b
ron
ch
""p;I~
m
in
pat
icnt
~
~i
th
asthnla
and they should
aH
lid l}-bllx:kcn Snm e l}-bl

t
:ke
r
~
po.
1
SSl'
S ~
i
lltrillxi

sl'mpulllOlllinWlic
(/I"lhity
(i,e, ;I T!.'
ra
ni al "gnnists, Chapter 2), The clin-
ical impon:
mce
of lhis
i~
dehu (;lhle, bul see Chapter 16,
10
Ocular
pharmacology
Cat
a
ract
form
atio
n

Retina
Ciliary pody
"'GE
~ E
L
A
fE
D
MAC
ULA~
DEGEN,
EI1AnON("'MDl
veruporfin
KEl lNDrA f HY
chloroquine
dia~ete!5
hyPerte
n5ion
11
1
13
11
oxyqen
te ne'cn in babi
e!5
~
·
I'
LOc:
I;.

E
R
S
timolal

112 -I'.GONI5T
br
imonid ine
- , CA INHIBITORS
a
cet
azolamide
dorzolami
d(":
wI!AGOMST
• c:pine
phrine
I'llI
'>OC
cM
t ri
cto
r
"
." "-
-


Cil
iary

mU6cl e
cortiCOl>teroi& ,
irrevcroit:>le
8ntic
holinee
U'
r
S5ef>
ateeecee
Anterior
~
h

m"r
Ciliary mu&cle
local a oaee
tbence
f1uore~in
a
nt
ibiot icei
a nt iviral dl1.l
'3l>

ntl-
i
nfla
mm
ato
ry

d rug",
Cornea
cYCLOPLE61CS
(
par
~ly;e
m!,lt'iClc:)
at ropine
tro
picamlde
cyclopeetotsre
CONTRACT{epaem)
pllocllrplne
ca
rt:>
achol
eccthiopate
The
~
)'
c
is
<In
inflated
spherical
shelf,
i
l
~
OUI"'f

layer hc ing th",
tough.
ccllagcn. nch sclera. The normal illlnu/I.
'ular
pre
s
sur
e
nOP
)
i~
about
15 mmHg and b muimu incd by ubuluncc
of
aqueoushumour formauon
b)
'
the
riliarv
"'1<
/
.1'
(. )and outflow throu gh the trohccutnr
mesh

ork
into lhe canal t1fSchlcmm i
__
), In
open

-angle
~
I
au{
'
n
ma
.
the lO P
rem
ains
abtlve::!-t mmUg be
ca
use pal
hulug
ical cha
nge'
inthe
uabe
cu-
lar meshwork decrease the
outflow
tlf
aque
ous
. Because the elevated
lOP
will eve urually
dama
ge the

optic
nerv e, the pressure is reduced.
usuall y
with
,[rugs . This can he achieved
either
by incrc
,in
g uqucous
outflow with mus
carini
c
a~
nni
s
"
.
such a.' " ilul
:arp
inc t
bottom
ld t),
or by rcdu
dn
g aq ucou -,
tormauon
with a
-e
an
ety of drugs (middll' right)

b UI es
pecially
tinmlnl
, a
~-
bl
od
er.
At the rrom Ilf the eye, the sclera ru
n,
intoth
e cor-n
ea
IllIp
[dO

host:
tr
ansp
arenc
y i,
obtained
by ulignmcm of the
collagen
Iihrev.
~hn
y
superficialmanipulations. such ,I'tonometry tmeasurcmcnt of the lOP )
and the removal Ill'corneal foreign bodies. r
equir

e the instillation
of
a [m·,,1anarsthrtic.
Huo
r
e-ccm
i~
commonly invtillcd inlll thc C)'Cto
reve al
dam
agod are av
of
cornea l epithelium, which are ' l:lined bri
ght
gree
n by the dye. Infla mmal it'n
of
the
cornea
resulting from allergy
('I'
dwm
il·al
bums
i>treated with topical anti-inflammatory
drugs
(Chap
ter
33), lnte
ction

s are not treated with unu-intlamnnuory agents except
together

ith an effective chemotherapeutic ilgent because anti-
inn amnl iuory d
mgs
red uce recistunce to invadi ng
microo
rganisms.
The ir
i,
[middle
rem
11I"
'><:
'
'><:
s a sphinc
ter
muccle. which receives
parav
ympath
ctic n
erve
s, and a d ilator
muscle
. which is innervated by
sympathetic fibres. Th us muscarinic antugonixtv ,
ulli
n-adrenoccpror

agoll
i'h
dilllie the pupil (rIIJdr i
a,
isJ. whil e mus
cnrjnic
agllnisls and u -
adrcnoc cpt
or
antagonicts ranstrict the p
upilt
mi nsi, ),
Corura
cuon
of the
par
;\Sympathcl ically innervated d li,lrJ mu
sd
e
(t'
IlIW
IU Id t) allows the lens to
beco
me thicker and acco
mr
noda
non
fur
ncar \
·i,

iull
I)CC
IlI'S.
·
11
111
~
.
muscarinic
ama
gonish ,,,
,m!.nf'
the ciliary
muscle
(("J
d
ll
p
l
t'~h
l)
,
HI
d prevent accommodation for n
car
vixiou.

hilc ugonists caust'
nccommodatien
and a loss

of
far vision.
The I('ns
(middle
top
j provide s the adjustable part
of
the ey
e's
refrac-
tive po er. Opacity of the lens is called a cataract. Smile drugs, nota bly
corticc
tcroids,
may cuusc cutaructs.
2.
The r
etin
a is " pnrt (If rhc c
entra
l nervous sys tem
hUI
it see rnv lilll.:
affected hy drugs, probably Ocl',
IU""::
of
the
euecuve
blo
od -rcrinul har-
rier. \"t'rf t'

po
rli n is a new llrug used 10 lreal age-related mac
ular
degcn
-
C ilia r)' hcd y
The
pTtlce, scs
of
the ciliary bo
dy
are highly
vascu
larized and arc the
sil':s of aq ueo us humou r formntien. The l;iliar} epilhl'lial cells. which
c
onnun
ATPase arul ca
rto
mc anh ydrasc. abs
orb
Na+ selectively From
the
st
roma
and trans port it unothe intercellular clefts, whic h
open
only
on the aq
ueo

us h
umo
ur side. The hypercs molality in the clefts cuuscv
water
no w from tile sar
omu.
pr
oducing a c
onnnu
ous flow of
aqueous
.
The
ci liary epithelium
i,
leak y. all
owin
g significant p a ive titrrunon.
and up
ttl JO%
of
aqueou s may he form ed by ut
trafiluuuon
.
Tr
abe
cu
t
ar
IlIl".h

'lur
k
The aqueous humour circulate- t
hrou
gh the pupil and isd rained i
ntothe
canal
nf
S
chlcnun
, which is a
circ
ular gutter within the surface of the
scient u
tthe
limh
u The sieve-Hke trabec ul ar mes hwork is the r
oof
of
the
gutte
r. th
rough
which the
OI
IJUt."t
lllSmust pa before il is
eve
ntually
draine

d away into the episclcrul ve ins.
Glaucom
a
Thi s h a group of oc
ular
diseases with the common features of ab
nor
-
mall y high lOP
and ultimate 10
of
vision if untreated. It II\:
CUrs
in ,thout
1%
otpeopt
e over 40 years
of
age.
view
ed
throu
gh an
ophth
almoscope
.
the
optic disc a
pJlc '
ars ocpre sed

(cup
ping) becaus

of th

lo
,;.
s
of
nen e
fibn.·s. The
rne
chanicm
by which the nerve fibres are des troyed in
glauco ma is
und
ear
, bltl ma y invulve
l11
edlal1i
<:a
l fal'tnrs amI/or It
l\:l\1
Ischa,
'mi
".
0Jlc 'n
-angle (chronic simple) glau<:oma Is lhe tllo
,;.l
COml11lln

form of lh

di

,, e. In clos
ed
-angle
glauc
oma, Ihe ang le hel\\t n Ihe
conlL'a " nd
the iris is ,Ibnormally small.
o.
;casionall)', the angle c1uses
completely.
prev
t-
'nlin
g ;KluelJus outfl ow. ;
Ul
d the 10 1' <Iuickl)' rises,
Bt'cause
IX'
nn
anenl da
ma
ge 10 lhc n:lina can occu r d
uring
the ::
allal.:ks.
the

pn:,s
ure mU,1he reduced
a
~
t.j
uil·kly a"!",-"sIblc by illU'flsi!'e imlifl<l-
(;0
/1
of
l'i!o('jlrpiIW
e)'edrops l·olJlhined. if necessary. with intr.tvenous
lI{'{'(lI
:olll
tl/i
de and
i
l1l
ra
v e
n
tl
u~
hYl
lI'rto
nic
lII
all
n
ito
l (an l

'lS
molic agelll ),
to renlllve waler. Ace
tal
olamide inhibits
ca
rhonie ,tnhydrdsc in lhe
ciliary
hody and
preve
nts bi
cal'fMln
ale synthesis. Th is leads to a fall in
sod ium
lranspon
and a'l ueom f
nn
nati nn
lM
.'eau se hicltrhnnalc and
soclium transport ,lI't:
linked,
PiI'
K:
ll
rpir
w. heing " lertiary amine.
dif
fuse-s readily Ihrough tile
co

rnea illln Ihe :l'lu<
'nus
humuur. II red
UC
t-'S
the lOP hy o;onlraet ing the
ciliary
nm,cl

. Th is pulls the scleral spur ;md rcsulls in the lrahe
e '
ular
meshwork being strl'tcheJ
and
M."
paraled. The fluid p,llhways arc
oJlc '
nl-'d up and
aqueous
oUlllow is increaseJ . All par.tsymp'llhomimet-
ic,;.
cau""
miosis. n.'sult ing in pon r nighl visinn and
l"< m
rl
airll"
of
'dim-
ming
of

vision '. Ci liary
m
u~
d
e
spasm that incTt'ases nl·ar-sightedne
causing nlurred
v
i~
i
o
l1
is not usually a pronlcm in lhe ;lge group lhat
de-
\'c1op
glauco
ma but can cuu"" headache and
brow'
ll·he.
Some
p
<.l
ti

nls lind lhe e
ef
fl-
'I:ts inlolerunte.
!J.llhll
."

kers. Ti
mo
lul is the drug
of
choice in upen-anl!.k glaUnll\1a.
[t
bl
o
l.
·k
~
13
2-adrenol.·epl ors on lh<' ciliary prll\:es;,cs anti so red uces
aqUC'I
'us
"I.'Crc
lion. In addit ion. lim olol ml
lY
nlock
!'S
-fCl
'ep
lo
!");
in the
aff
eren
t h
llMxi
vessels , up

pl)
'ing the cilial1'
proce
es. The resulling
vasocllm lr
il.'
liun resuh s in rCllul.'l·d ultrafiltrat ion amI ,lq
Ue-
OIlS
fnnna
-
lion . T imolol avoids lhe unpl easant effecls of pil
oca
rpin<' on the eye ,
hut
it is
ahsorI:>W
syslemiea
lly and may
provo
ke bnlll
eho
spasm in
asthmalics or
br
d
dyca
rdia in s
ll'oCe
ptibk pali cnts. Th

C'
TI
.'f
ol'C'
.l3-hlo
ch
·rs
c
nuiou
(AMD). Th e retina rnay occaviuually be
damag
ed by dru p te.g.
b
onum
rightIor by high
oxyge
n tenvlon in new born hallies.
tcvcn selective I3I-a
l11
agonisIS) should he avoided in p.uicnr s with
aslhma. hear! failure. heart blo
ck
or
bradycardia .
l.at
anop
ne- t is a pru
dru
g o f prust;lgl;mdin-F
2

. The drug passes
through the c
om
ca and re
duce
s the [
01'
hy increasin g the uvcosclerat
outflow
of
aqueous.
Epin
eph
rilll
' tudrennlinc) and rr-adrcnoc
cptor
vtimularus lower the
1
01'
b)
' an u .mcdiated vasocon-aricuon of lhe d lial')' body arrcrcm
nl
lM
lll ves sels, Co nfusingly. u -
anta
goni sls and
13
-,ulrenoceplOr agonisls
respcci ally
1i

2
"Slimulanls) also lower the
10
1'. These dru gs increase the
omno
w of aq ucous rather than reduc ing il;, form
auon.
pres umably by
dilatation o f lhe a
queo
us vei
n,;.
and/or
ep
iscleral
wins
.
IIr im
unidin
l'
and
apruclunidiue arc u
2
-adrcm
M:
epIUr
agonist
s. They
d
ecr

eas
e aqueou s formation h)' stimulating ({2-
TC
"
cpw
rs on the udre-
nc rgic nerve terminals innervating the
cihury body
(lIIU
s reducing nor-
epinephrine rctca-e j.
Illlr
wiami
dl.' is a top icall y active inhibitor of
carbon
ic anhydrase
(CA-21.
It can he used alone in paricms in
whom
ii-bin
de
rs arc con-
truin
dicated
. It is a sulp
honamide
and syste mic side-effects may occur.
c.g. s"i n rashes, bron
cho
spas m.

Las
er Ir-
ah
e
culur
suq
:ery
may be u
,e
d as an ancrnauvc
\0
drugs in
gfuucom a.
Under lo
cal
aruu-crhesiu. the urgeon use-,an argon or dilx!

la

r 10 place ahtlUl 100
eve
nly s
paced
lesion, on the ioncr surface
of
the trabecula r
meshw
ork.
'I11
1.

· laser ' hu
m,
' cau ,C'
k><:
alilt':d shrinkage.
whidt
cxcns
ll'n~ion
on lhe adj,!t·elll. unt r
ealed
tissue. olX'ning sp,tccs
in lhl' me
shw
ork and allowing incrl
'a,
ed
l
l
q U
e-O
U.~
dr
;linage. In
close
d-
anj!.k glaul
'om
a, an )'llrium alu minium ga
nw
t (YAG

ll
a ermay be u""d
10 make a hole
01
1 lhe periphery of lhe iris. Thi s prcvellls the forward
mo
wtllent
of
the iris lhm pl'e
cipitatl
's
an
ne-
gla
Ul'
ollla anti is uSllally
causl'd
by a pan ial block Ill'
a'
lueous llow Ihrou gh lhe pup il.
While lhe
hc 'nclil\ of trcating paliellls wilh closed-angle glaucoma are
d ear, the same cannot he Iid fur pati ent s with 1l
Jlt,
'n-ang1e gla
uo;
oma ,
",-'C
ause the availahle evidence dol'Sm,t
c

'
ll
lvi
ne '
i
n ~
l
y
show lhat lrcatmcnt
wilh drugs or la

r surgery an

-cb the long-t
enn
progre
,;.
s u
fl
be disca e.
Mydriatics
M
ydria
SiS(dilatation
of
the pupil )is rcquin'd for
ophthalmo
scopy. The
drops most
com

monly used arc the
rc1<
ilivcly shllrt-al'ling mU
'oC
"r
inic
a
mago
nis" Ir
np
k
am
ide and
('~
dll
pt'
n
lf)
h
l
le
,
which prlx!uce
rol
h my-
d
ria
si
~
"nd

cycloplegia. The
1.t
-
adrcno
l.·l'pIOr stimul ant
I
lh
en
~
1l'Ilh rine
may
tM:
used to
pn
xiuee mydri;tsis wilhuUI :lffec ling lh
e '
pupill ;lry light
I'I."tk\
or
acco
mrnlx!
alio
n. Myd riasis ilia)' precipilate a
>:u
te c1oscd -angk
glauo;olll,l
in s
u ::ep
lin1epatil'nls who lire usually
agl

'l.lllw
r
60
yea
Age-related
macular
de
g
eneration
-'
!!eo
rda
l
ed
mm
;u
la r de!!elW
ralion
(
-'
\ 11))
affectsn
lOcrp.:
np
le and is
the most
eommlln >:ause of hlim
lne,s
in Ih UK.
Nl'lIo

' hlol
l<!
\'e el
fonn
unl!<:r
the
re-
tina
;lI1d
Ie;l
f."
age
of
lluid and hlood frum the vaWlllar
c
o
m
ple
\
e~
c a
u~e
""veTt' loss of
v
i~
i
ll
n
within a few years. Verl l.·Il<,rlin
i,;.

a lighl-
::n
sitivc dye th"l is given inlra
wnuu
sly and is laken up hy the
v;\'oCul
ar endolheliullI. A la,,-'r is then applie
<l
lo the Il'siol1and this aCli-
vales
the dye. releasing IOxi
>:
free radil.'als that dcstroy the new
\'C~s
e
ls
(pho
l,l<!y
na
mic
therapy), The eflicacy {Ifthis imcresling I
rcalm
cnl has
ye
li
ll he eSlablished b
UI
it
"l
nls to be most effec live in palielll s with

d a" ic
~
u
hfo
vC'a
l
ol.·{lva
::ula
ri/.ation.
27